Safety Profile Assessment of Risperidone and Olanzapine in Long-Term Care Patients with Dementia

Transcription

1 ORIGINAL STUDIES Safety Profile Assessment of Risperidone and Olanzapine in Long-Term Care Patients with Dementia Harlan Martin, RPh, CCP, FASCP, Michael P. Slyk, PharmD, FASCP, Sheila Deymann, PharmD, FASCP, and Mario J. Cornacchione, DO, CMD Objective: To assess the adverse events associated with the appropriate use of oral risperidone and oral olanzapine in long-term care patients with behavioral and psychotic disturbances associated with dementia. Design: Observational analysis. Setting: Analysis was performed at five consulting pharmacist sites across the United States. Participants were recruited at 89 skilled nursing facilities by consultant pharmacists who provided services at each site. Patients: A total of 730 men and women with dementia who had been residents of a skilled nursing facility for at least 90 days were included in the study. Alzheimer s disease was the primary diagnosis in 47% of patients. Intervention: Patients were treated with risperidone 2 mg/ day or olanzapine 10 mg/day for at least 90 days. Measurements: Targets for antipsychotic use included nonaggressive symptoms of psychosis and verbally and physically aggressive behaviors. The effects of risperidone and olanzapine were determined from progress notes, psychotropic monitoring forms, and physicians order forms after 91 days of treatment. Adverse events of particular significance in the elderly population, including agitation/anxiety, laxative use, dry eyes, and falls, were collected from audited medical records. The evaluation period extended from 3 months before to 3 months after initiation of treatment with risperidone or olanzapine. Results: There were 474 patients in the risperidone group and 256 patients in the olanzapine group. Mean dosages of risperidone at Days 1 and 91 ( mg/day and mg/day, respectively) and olanzapine ( mg/day and mg/day, respectively) were at least 50% lower than the maximum dosages recommended by the Center for Medicare and Medicaid Services for elderly patients with psychosis or behavioral symptoms of dementia. The need for eye lubrication was minimal in both groups and did not differ significantly between them. Anxiolytic use decreased in the risperidone group and remained constant in the olanzapine group, with no significant difference between groups. In the olanzapine and risperidone groups, the number of patients with orders for laxatives increased 10.2% and 1.8%, respectively (P 0.003), the mean number of days of laxative administration increased 19.1% and 4.3%, respectively (P 0.001), and the mean number of doses of laxative administered increased 14.2% and 4.1%, respectively (P 0.001). Among patients qualifying for analysis, falls were recorded for 17.9% of patients receiving olanzapine and 6.9% receiving risperidone (P 0.001). Conclusion: Among long-term care residents with dementia who received low doses of risperidone or olanzapine, the incidence of adverse events was low. When considering adverse events of particular concern in the elderly, specifically falls and laxative use, risperidone may be preferred over olanzapine in this population. (J Am Med Dir Assoc 2003; 4: ) Keywords: antipsychotics; dementia; olanzapine; risperidone; safety Creative Care Consulting, Clark, New Jersey (H.M., S.D.); Pharmacotherapy Associates, Inc., Warren, Ohio (M.P.S.); and Geriatric Research and Consulting Group, Wilkes-Barre, Pennsylvania (M.J.C.) Supported by Janssen Pharmaceutica Products, L.P. Address correspondence to Harlan Martin, RPh, CCP, FASCP, Creative Care Consulting, 136 Central Ave, Clark, NJ Copyright 2003 American Medical Directors Association DOI: /01.JAM Elderly patients are particularly at risk for certain drug-related adverse events because of polypharmacy and the physiologic changes associated with aging, including decreased renal function and changes in enzyme systems 1 and neurotransmitters. 2 In general, atypical antipsychotics can control psychotic symptoms and behavioral disturbances in elderly patients with dementia or schizophrenia. 3 5 However, the adverse events associated with these agents are of particular concern in the elderly, especially among those who require nursing home care. Quality indicators (QIs) derived from the Minimum Data Set were established to help long-term care facilities and surveyors identify areas in which a facility may be providing poor quality care. How an individual facility performs on many of the QIs is directly or indirectly related to how well it manages common geriatric syndromes and diseases, including ORIGINAL STUDIES Martin et al. 183

2 behavioral disturbances and psychotic symptoms associated with dementia. Drugs used as therapy for behavioral disturbances associated with dementia can affect QIs, such as prevalence of fecal impaction, by virtue of their anticholinergic effects, and falls due to their association with adverse events such as extrapyramidal symptoms (EPSs), orthostasis, sedation, and gait disturbance. Clinical trials of atypical antipsychotics in mixed-age populations of adults with schizophrenia may provide incomplete information regarding the safety of antipsychotics in elderly long-term care patients with dementia. The objective of our observational study was to assess adverse events of particular concern in elderly long-term care residents associated with the real-world use of risperidone and olanzapine. METHODS The study was conducted from September 23, 1999, to October 15, 2000, at five sites in the United States: Pharma- Care, Inc., Clark, New Jersey; Pharmacotherapy Associates, Inc., Warren, Ohio; Institutional Pharmacy Consultants, Inc., Griffin, Georgia; Mark Sey and Associates, Inc., Woodbridge, California; and Innovative Health Care Solutions, Yorktown, Virginia. A consultant pharmacist routinely providing services to a particular site recruited long-term care facilities at each site. Eighty-nine long-term care facilities participated in the study. Patients Patient inclusion criteria included residence in a skilled nursing facility for 90 days; age 55 years or older; Alzheimer s type, vascular, or mixed dementia as evidenced by functional decline documented in a patient s clinical record or determined by the Functional Assessment Tool 7 ; and treatment with risperidone 2 mg/day or olanzapine 10 mg/day for psychosis or behavioral symptoms associated with dementia. Exclusion criteria were diagnosis of Parkinson s disease, medication for Parkinson s disease or essential tremor, or as-needed antipsychotics as primary treatment. Residents were screened by clinical observers to reach an equivalent sample size for those receiving risperidone or olanzapine. Design The study was a retrospective chart review. After identification, patients were assigned to one of two treatment groups. Patients received risperidone 0.5, 1, or 2 mg/day or olanzapine 2.5, 5, or 10 mg/day for behavioral symptoms of dementia. Clinical Research and Development Corporation, Inc., was contracted as an independent institutional review board to provide a third-party protocol review. To ensure anonymity, long-term care facilities and patients were identified by code during that investigation. The medication record of residents meeting the inclusion criteria was reviewed for 6 months by a consultant pharmacist. Medical records were evaluated for 3 months before and 3 months after the start of either risperidone or olanzapine treatment. Data were collected from physicians and nurses progress notes, psychotropic monitoring forms, and physicians order forms. These data were used to complete a standardized data collection form. Categories on this form included demographic data, type of dementia diagnosis, concurrent psychiatric diagnosis, concomitant disease/condition, target behaviors for antipsychotic use, nonaggressive symptoms related to dementia, nonpharmacologic management of target behaviors, reason for antipsychotic use, concurrent pharmacologic therapy, current antipsychotic use, previous antipsychotic exposure, antipsychotic adverse events, and management of antipsychotic adverse events. Outcomes Selected adverse events for review were chosen based on their expected rate of occurrence, as indicated in the product literature for each antipsychotic, or on their ability to be documented with relative accuracy in a medical record. The addition of or increase in the dosage of medical therapy to control the adverse events was used as an indicator of their occurrence. Agitation or anxiety was assessed by evaluating the addition of or increase in the use of anxiolytics 7 days after initiation of antipsychotic treatment compared with use 7 days before treatment initiation. Anticholinergic effects were measured by evaluating constipation and dry eyes during the 7 days before and during the last 7 days of treatment with risperidone or olanzapine. Change in laxative use was determined by comparing the number of patients with orders for laxatives, the number of days on which laxatives were administered, and the total number of laxative doses per patient that were required for maintaining normal bowel function. The frequency of dry eyes was measured by evaluating the addition of or increase in use of lubricating ophthalmic drops. Falls were assessed by comparing incidence of falls within 3 months before and 3 months after risperidone or olanzapine was started. Use of physical restraints to prevent falls was noted and accounted for in the analysis. Data Analysis Exploratory data analysis techniques, including summary statistics, were used to summarize and confirm the quality of the data. Baseline differences between the two groups were assessed using the t test. Significant differences in adverse events between treatment groups were assessed using Fisher s exact test and chi-square analysis. Repeated-measures analysis of variance was used to assess between- and within-treatment effects. Variables included demographic data, the types of dementia diagnosis, concomitant disease states or conditions, target behaviors, psychiatric symptoms, antipsychotic-induced adverse events, management of antipsychotic adverse events, and reasons for antipsychotic use. RESULTS A total of 11,952 patients were screened. Patients were matched for age, race, dementia diagnosis, concurrent psychotic diagnosis, target behaviors, and payer status. Data were analyzed from 730 patients: 474 in the risperidone group and 256 in the olanzapine group (Table 1). Mean age was years (range years), and age distribution was 184 Martin et al. JAMDA July/August 2003

3 Table 1. Baseline Demographic and Clinical Characteristics Risperidone (n 474) Olanzapine (n 256) Age (yr); mean (range) 79 (57 106) 78 (55 104) Sex (n female) Race (%) Male Female Male Female White Black Hispanic Asian Other Dementia diagnosis (%) Alzheimer s disease Vascular dementia Mixed dementia Other Concurrent psychotic diagnosis (%)* Delusional disorder Psychosis Schizophrenia Bipolar disorder Concomitant depression diagnosis (%)* Payer status (%) Private Medicare A Medicaid Insurance/other *As of the date the drug was prescribed. similar between groups. The most common dementia diagnosis was Alzheimer s dementia (47% of patients). Concurrent diagnosis of delusional disorder was equally represented in both groups. A 4.4% differential for psychosis and a 1.4% differential in bipolar disorder diagnoses occurred between treatment groups, and more patients in the olanzapine group (7.0%) than in the risperidone group (3.4%) had a diagnosis of schizophrenia. A total of 135 patients in the risperidone group (28.5%) and 84 in the olanzapine group (32.8%) had previously received antipsychotics; 25.6% and 22.7% of the risperidone and olanzapine groups, respectively, had previously received conventional antipsychotics. The most common nonaggressive behaviors related to dementia were repetitive actions in risperidone patients (42.6% vs 32.1% for olanzapine) and paranoia/delusions/hallucinations in olanzapine patients (46.5% vs 41.8% for risperidone) (Table 2). Antipsychotic drugs were given primarily for issues relating to self-endangerment (risperidone 21.1%, olanzapine 25.8%), provision of care (risperidone 56.3%, olanzapine 61.3%), resident safety (risperidone 45.1%, olanzapine 35.6%), and endangerment of others (risperidone 42.8%, olanzapine 35.6%). Mean risperidone dosages initially and at Day 91 were mg/day and mg/day, respectively. Mean olanzapine dosages initially and at Day 91 were mg/day and mg/day, respectively. Agitation and Anxiety A total of 730 patients were included in the agitation/ anxiety analysis. Anxiolytics were used 7 days before the start of antipsychotic treatment by 138 patients (29.1%) in the risperidone group and 79 patients (30.9%) in the olanzapine group. Changes in agitation/anxiety, as measured by increases in use of an anxiolytic at 7 days after initiation of treatment with risperidone or olanzapine, decreased 3.4% in the risperidone group and remained unchanged in the olanzapine group. The difference between groups was not statistically significant (P 0.110) (Table 3). Anticholinergic Effects The increase from the 7-day period before starting antipsychotic therapy (pretreatment) to the last week of the study period in the percentage of patients with orders for laxatives was 5 times greater in the olanzapine group than in the risperidone group (P 0.003) (Table 4). The percentage of patients in the risperidone group with orders for laxatives did not increase significantly from pretreatment (198 patients [41.9%]) to the last treatment week (207 patients [43.7%] (P 0.238). In the olanzapine group, the percentage increase in laxative orders was significant (111 patients [43.4%] and 137 patients [53.5%] at pretreatment and last treatment week, respectively; P 0.001). The mean number of days a laxative was administered increased 4.3% (2.57 and 2.68 days at pretreatment and last treatment week, respectively) in the risperidone group and 19.1% (2.77 and 3.30 days at pretreatment and last treatment week, respectively) in the olanzapine group (P 0.001). The increase in the mean number of doses of laxative administered over a 7-day period was 4.1% (3.70 and 3.85 doses at pretreatment and last week of treatment, respectively) in the risperidone group and 14.2% (4.58 and ORIGINAL STUDIES Martin et al. 185

4 Table 2. Target Behaviors and Reasons for Antipsychotic Use Risperidone (n 474) Olanzapine (n 256) Target behaviors (%) Verbal aggression Screaming/yelling Cursing/vulgarity Repetitive verbalization Threatening accusations Crying out Physical aggression Self-injury Object throwing Inappropriate sexual behavior Pinching Kicking Hitting Nonaggressive symptoms related to dementia Social withdrawal Pacing/wandering Paranoia/delusions/hallucinations Repetitive actions Sleep disturbances Reasons for antipsychotic use (%) Self-endangerment Danger to others Interferes with care Issue of resident safety at pretreatment and last treatment week, respectively) in the olanzapine group (P 0.001). Eye lubricant use was minimal in both treatment groups, and there was no significant between-group difference in the change from pretreatment levels. The percentage of patients using eye lubricants increased 2.1% (23 and 33 patients pretreatment and last week, respectively) in the risperidone group and 0.6% (18 and 21 patients at pretreatment and last week, respectively) in the olanzapine group (P 0.372) (Table 3). The average number of daily doses received per participant increased from 0.59 to 0.64 (7.9%) in the risperidone group and from 0.58 to 0.75 (29.7%) in the olanzapine group (P 0.417). Falls Patients with no history of falls or osteoporosis and no use of restraints before antipsychotic use were included in the final analysis; 232 patients in the risperidone group and 128 in the olanzapine group met these criteria. The percentage of patients who fell within the first 3 months of treatment was approximately 2.5 times greater in the olanzapine group than in the risperidone group (6.9% vs 17.9% for risperidone and olanzapine, respectively; P (Table 4). More than one fall occurred in 7.8% of olanzapine patients and 3.0% of risperidone patients (P 0.033). Analysis of the cohort with no prior history of falls revealed no differences between the demographic profiles of patients who fell and those who did not fall. In addition, the treatment groups were similar with respect to other factors associated with falls, including use of antidepressants, anxiolytics, and beta-blockers and concomitant disease states, including hearing and vision impairment and seizures. Also, concomitant psychotic or depression diagnoses were not related to falls. The incidence of falls was not dose dependent within the dose range administered. DISCUSSION This study was designed to assess the safety profiles of risperidone and olanzapine in elderly long-term care residents with dementia. We found that appropriate low doses of risperidone or olanzapine are used in this population and that Table 3. Percentage Change from Baseline in Indicators of Adverse Events for Which There Was No Statistically Significant Difference Between Treatment Groups Indicator of Adverse Event Risperidone (n 474) Olanzapine (n 256) P Anxiolytic use Eye lubricant use No. of patients using eye lubricant % increase in average daily doses per patient Martin et al. JAMDA July/August 2003

5 Table 4. Adverse Events for Which There Was a Statistically Significant Difference Between Treatment Groups Risperidone (n 474) Olanzapine (n 256) P Laxative use No. (%) of patients with laxative orders Pretreatment week 198 (41.9) 111 (43.4) Last treatment week 207 (43.7) 137 (53.5) Percent increase Mean no. of days of laxative administration Pretreatment week Last treatment week % increase Mean no. of laxative doses administered Pretreatment week Last treatment week % increase Falls No. (%) of patients who fell during the treatment period* Total no. of patients who fell 16 (6.9) 23 (17.9) Patients with 1 fall 7 (3.0) 10 (7.8) *Patients with osteoporosis, physical restraints, or previous falls were excluded; n 232 risperidone, n 128 olanzapine. the incidence of adverse events of particular concern in these patients is generally low. In this study, the mean dosage of risperidone and olanzapine 91 days after treatment initiation was mg/day and mg/day, respectively. These dosages are lower than those recommended by the Center for Medicare and Medicaid Services guidelines for this patient population (2 mg/day and 10 mg/day, respectively) 8 but are consistent with findings in previous clinical trials. 3,4,9 11 Because some adverse effects of these drugs are dose dependent, treatment with the lowest effective dose in this population is desirable. 12,13 The adverse events evaluated in our study are among those that are especially prevalent among elderly long-term care residents. Some of these adverse events are specified as QIs (ie, falls and anxiolytic use) or closely related to QIs (ie, laxative use, related QI fecal impaction) for nursing homes. 6 The use of eye lubricants was studied as an additional indicator of anticholinergic effects, also an area of particular concern in the elderly. 2 In general, the change from pretreatment incidence of adverse events in this study was small. Anxiolytic prescriptions decreased 3.4% in the risperidone group and remained unchanged in the olanzapine group. The increase in incidence of dry eye was also low, occurring in 2.1% and 0.6% of the risperidone and olanzapine groups, respectively. There were no significant differences between the two treatment groups with respect to these events. Constipation is highly prevalent among elderly nursing home residents, 14 is often related to use of anticholinergic medications, 15 and can adversely affect quality of life. 16 In our study, significant differences from baseline occurred in laxative use only in the olanzapine group, and the increase in this adverse event also differed significantly between treatment groups. The increase in the percent of patients requiring laxatives was fivefold greater in the olanzapine group than in the risperidone group. The change from baseline in laxative use was statistically significant only in the olanzapine group, and the change in mean number of days and mean number of doses of laxative administration were significantly greater in the olanzapine group than in the risperidone group (P 0.001). The number of patients who fell was significantly greater in the olanzapine group than in the risperidone group (P 0.001). The number of patients experiencing falls has been reported as no different from placebo in elderly nursing home residents taking risperidone 0.5, 1, or 2 mg/day. 3 Although the incidence of falls was not reported separately, accidental injury, including falls and fractures, was reported as not significantly different from that seen with placebo in patients taking olanzapine 5, 10, or 15 mg/day. 11 Further studies are necessary to understand this issue, as no specific predictors were identified among those we studied, including previous history of falls, concomitant medications, and concomitant psychiatric symptoms or diagnoses. We did not evaluate concomitant use of antihypertensive medications other than beta-blockers; these agents may be a confounding factor with respect to falls. The mechanisms by which psychotropic medications increase risk of falls include sedation, orthostatic hypotension, abnormal gait, weakness, impaired balance, and anticholinergic effects such as blurred vision, urinary incontinence, drowsiness, and delirium. 2,17 19 Differences in anticholinergic effects may have contributed to the difference in falls seen in our study. Although we did not measure sedation, the fact that the affinity of olanzapine for histamine-h 1 receptors, which are associated with sedation, is greater than that of risperidone 20 suggests that differences in incidence of sedation might contribute to differences in incidence of falls. The incidence of somnolence has been reported as significantly greater with olanzapine 5 to 15 mg/day than with placebo among elderly nursing home residents. 4,11 In the same studies, the incidence of abnormal gait was reported to be greater than that with placebo in residents taking olanzapine 5 and 15 mg/day 4,11 ; approximately 30% of patients with somnolence ORIGINAL STUDIES Martin et al. 187

6 also had abnormal gait. Dose-dependent 3 and overall somnolence 9 was also reported as greater in elderly nursing home residents taking risperidone compared with placebo. No data from controlled comparative studies of risperidone and olanzapine have been published in this population. The difference between the anticholinergic effects of risperidone and olanzapine as measured by the increase in laxative use in our study is consistent with differences in the respective muscarinic-m 1 receptor binding of these agents. 20 Pooled peripheral anticholinergic-mediated adverse events, including constipation, were reported to be greater with olanzapine 15 mg/day than with placebo in an elderly nursing home population. 11 However, no significant difference from placebo was noted in individual adverse events related to anticholinergic activity, including constipation. Anticholinergic effects of risperidone were no different from those seen with placebo in an elderly nursing home population in a clinical trial. 9 Further studies may be necessary to elucidate comparative clinical anticholinergic effects in this population. We did not control for other contributing factors to constipation, such as immobility and medication (ie, analgesics), in our study. Our study is limited by its short duration (91 days) and its retrospective, uncontrolled, naturalistic design. Adverse events addressed were limited to a small number of those of particular importance in the nursing home setting and for which data were available. Other adverse events of potential importance in this setting, particularly other anticholinergic effects, such as somnolence, delirium, and changes in cognition, were not addressed. Because objective measures of EPS are not commonly used and documented in a clinical setting, our naturalistic retrospective study design did not allow for a valid determination of the presence of EPS in this study population; however, the incidence of EPS is low in the elderly population when these atypical antipsychotics are given at appropriate low doses. 3,9,11 CONCLUSION Appropriate low doses of atypical antipsychotics can be used with success in the long-term care setting in patients with dementia and behavioral disorders associated with psychosis. In our study, adverse events in elderly long-term care residents receiving appropriate low doses of risperidone or olanzapine were generally infrequent. The difference in the incidence of falls and anticholinergic effects as measured by laxative use suggests that low-dose risperidone may be a better choice than olanzapine in the elderly nursing home population. Further studies are needed to assess the relative effects of these and other atypical antipsychotics in these domains because adverse events can have a significant effect on the quality of life of these patients. REFERENCES 1. Nies AS, Spielberg SP. Principles of therapeutics. In: Hardman JG, Limbird LE, eds. Goodman & Gilman s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw-Hill, 1996, pp Peters NL. Snipping the thread of life: Antimuscarinic side effects of medications in the elderly. Arch Intern Med 1989;149: Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial. J Clin Psychiatry 1999;60: Clark WS, Street JS, Feldman PD, et al. The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer s disease. J Clin Psychiatry 2001;62: Daniel DG. Antipsychotic treatment of psychosis and agitation in the elderly. J Clin Psychiatry 2000;61(suppl 14): Center for Health Systems Research and Analysis. Facility Guide for the Nursing Home Quality Indicators. Madison, WI: University of Wisconsin, Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer s disease: Reliability, validity, and ordinality. Int Psychogeriatr 1992; 4(suppl 1): Gurvich T, Cunningham JA. Appropriate use of psychotropic drugs in nursing homes. Am Fam Physician 2000;61: De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53: Brodaty H, Grossman F, Bruynseels J. Risperidone in the treatment of agitation and psychosis and dementia. Presented at the Tenth Congress of the International Psychogeriatric Association, September 9 14, 2001, Nice, France. 11. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: A double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2000;57: Physician s Desk Reference, 56th edition. Montvale, NJ: Medical Economics, Williams R. Optimal dosing with risperidone: Updated recommendations. J Clin Psychiatry 2001;62: Harari D, Gurwitz JH, Avorn J, et al. Constipation: assessment and management in an institutionalized elderly population. J Am Geriatr Soc 1994;42: Monane M, Avorn J, Beers MH, et al. Anticholinergic drug use and bowel function in nursing home patients. Arch Intern Med 1993;153: Schaefer DC, Cheskin LJ. Constipation in the elderly. Am Fam Physician 1998;58: Cumming RG. Epidemiology of medication-related falls and fractures in the elderly. Drugs Aging 1998;12: Rubenstein LZ, Josephson KR, Robbins AS. Falls in the nursing home. Ann Intern Med 1994;121: Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home residents. Am J Med 2000;108: Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14: Martin et al. JAMDA July/August 2003