Are your behavioral intervention policies for persons with dementia up to the challenge of the increasingly complex benefit-to-risk evaluation?

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othing is more vexing for caregivers in long-term care facilities than uncontrolled behaviors. Nothing is more distressing to family and patients than difficult-to-treat behaviors associated with dementia. And nothing is more regulated in the nursing home environment than the use of antipsychotics to address these behaviors.
       It is estimated that as many as 78% of residents in a nursing home have dementia, and of these 76% suffer from behavioral and psychological symptoms of dementia (BPSD), with 40% showing 5 or more specific behaviors.¹ Centers for Medicare & Medicaid Services (CMS) Online Survey, Certification and Reporting (OSCAR) data for April 2006 show that 26.1% of nursing home residents receive an antipsychotic medication. Dementia is prevalent, as are the behaviors for which antipsychotic medications are commonly used. With the advent of the second-generation (ie, “atypical”) antipsychotics, practitioners were offered the promise of a reduced side-effects profile with continued efficacy in behavioral control.
       But recent data and regulatory actions created a cloud of doubt on the safety of these agents, specifically in the elderly and for conditions that are common comorbidities for elderly nursing home patients. In addition, none of these agents is Food and Drug Administration (FDA)-approved for controlling behaviors in patients with dementia, and the efficacy data are generally not robust. The multidisciplinary team is taking a second look at the risk-benefit dialogue relative to antipsychotic use. Let us explore the issue of efficacy and safety of these agents for long-term care patients.

Efficacy: What is the Evidence?

       As the treatment of dementia advances, our nomenclature must advance with it. We no longer document “organic brain syndrome” or “age-related senility.” Even the term “dementia” is becoming a throwaway diagnosis as we learn more about Alzheimer’s disease, Lewy-Body Dementia (LBD), frontal-temporal dementia (FTD), and the like. Similarly, our nomenclature of behavior must evolve. We should no longer discuss “agitation” or “aggression” as diagnoses but look at them as part of the dementia syndrome. In referring to general “behavioral disturbances,” the International Psychogeriatric Association in 1996 settled on the convention of BPSD; others have used “psychosis of dementia” to refer to specific psychotic behaviors related to a dementia diagnosis. No matter how we classify the diseases and the behaviors, we must have clarity on the evidence that suggests antipsychotics are efficacious if we are to have an informed assessment regarding their use.
       There is no FDA-approved medication for BPSD. The one attempt at approval was Johnson & Johnson’s FDA application for “psychosis associated with Alzheimer’s disease.” The application received a nonapprovable letter from the FDA in mid-2005. Neither Johnson & Johnson nor any other manufacturer of antipsychotics has pursued one since, and none seems likely to after a black-box warning for elderly patients.
       Researchers have looked at many of the efficacy studies for conventional antipsychotics in dementia and concluded that effects are consistent, but the treatment effect size over the placebo effect size in these studies has been modest. Only 59% of patients on active treatments showed improvement as compared to 41% of placebo-treated patients.^2,3 Atypical agents in the aggregate show even less of a response in some studies than do the conventional agents. Hemels et al⁴ reported an overall success rate in BPSD of 56.1% for atypical agents, 63.1% for conventional agents. Since the emergence of safety concerns, many authors continue to address the question of efficacy versus safety for elders and those with dementia.^5,6

Safety: What Are the Concerns?

       In reviewing Johnson & Johnson’s data for its indication application, the FDA noted that based on a pooled analysis of 4 placebo-controlled double-blind randomized trials of the atypical antipsychotic Risperdal^® (Janssen Pharmaceutica) in elderly patients with dementia-related psychosis, the incidence of serious cerebrovascular adverse events (CAEs) in a total of 1,230 patients was 1.6%, compared to 0.6% for patients not using Risperdal. Nonserious events also favored Risperdal users over nonusers—2.2% to 0.9%. The differences were statistically significant when all CAEs were pooled but not for serious CAEs. My evaluation of the studies suggests that the registration studies were used to determine safety and overall efficacy but not designed or able to determine a cause-and-effect relationship between the use of Risperdal and stroke-related events. Patients were included in these studies with a history of previous stroke and other risk factors predisposing to stroke. Based on these data, the FDA required the Risperdal label to be updated with a warning: “In placebo-controlled trials, there was a significantly higher incidence of [CAEs] in patients treated with risperidone compared to patients treated with placebo.” The FDA followed with more CAE warnings to the labels of Zyprexa^® (Eli Lilly and Co.) in 2004 and Abilify^® (Otsuka America Pharmaceutical, Inc.) in February 2005. Selected atypical antipsychotic labeling also contains warnings on alterations in glucose and lipid metabolism and prolongation of the QTc interval, further complicating therapy decisions for residents with diabetes and cardiovascular disease.
       While these warnings were serious, they did not rise to the level of the most stringent warning—the “black-box” warning of April 2005 that the FDA required all manufacturers of atypical antipsychotics to apply to their labeling. This warning reads: “Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6–1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared to about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. [Name of drug] is not approved for the treatment of patients with dementia-related psychosis.”
       Individual drug studies indicate that the variety of these deaths occurred in patients 85 years of age and above, those with upper respiratory infections, and those who use benzodiazepines. Schneider et al⁷ state that while concluding a 1% absolute increase in mortality of patients on the medication versus patients who were not in a meta-analysis of randomized placebo-controlled trials, “The increased risk only could be identified when the atypical drugs were combined in a meta-analysis. The meta-analysis of each drug was not statistically significant.” While the FDA has not yet mandated such a black-box warning on conventional antipsychotics, they do not seem spared from the increased risk. Wang et al⁸ performed a retrospective cohort study of 22,890 patients 65 years of age and above, published in 2005, in which they found that conventional antipsychotic medications were associated with a 37% higher adjusted risk of death than were atypicals. They concluded, “Conventional antipsychotic medications are at least as likely as atypical agents to increase the risk for death among elderly persons” and that “conventional drugs should not be used to replace atypical agents discontinued in response to the FDA warning.”
       In discussing this issue with me recently, a physician colleague summed up his thoughts thusly: “You want me to order an antipsychotic drug that has an incremental behavioral effectiveness [for demented elderly patients] of 18% to at best 30% and then tell me I have a two-fold relative risk of all-cause mortality?”
       Indeed, this is precisely the conversation that needs to take place based on the current data. Antipsychotics are efficacious for BPSD, which is prevalent in persons with dementia and can be life-threatening. Patients may be at risk for an increased (while low) incidence of all-cause mortality as well as complicating the course of their comorbid conditions, such as cardiovascular disease, diabetes, and cerebrovascular disease. This question is a good lead in to our next focus: the basis of a rational approach to use of antipsychotic agents in BPSD and the role of the consultant/senior care pharmacist in treating these behaviors.

How Do We Characterize Rational Use?

       Behavior is a symptom. Before we can discuss rational use of an antipsychotic for BPSD, we must be sure the patient has dementia. Behavior can be a result of unaddressed pain or a manifestation of a medication-related problem, a delirium, an organic lesion, an endocrine imbalance, etc. There are significant resources available regarding the differential diagnosis of dementia to guide our choices here. Once the diagnosis is made and other causes are ruled out, nonpharmacologic interventions are a first and continued step in the process to address the behavioral problems. These interventions include staff and environmental approaches for the cognitive and functional deficits of patients with dementia.
       In addition to nonpharmacological approaches, the treatment of the dementia itself can improve and maintain cognition, functionality, and behavior. Acetylcholinesterase inhibitors, such as Aricept® (Pfizer, Inc.), Exelon^® (Novartis), Razadyne^® ER (Ortho-McNeil Neurologies, Inc.), and the NMDA receptor antagonist Namenda^® (Forest Pharmaceuticals, Inc.) have shown improvement in functionality, behavior, and, in some cases, a reduction or discontinuation of antipsychotic therapy due to improvement in BPSD. Edwards et al⁹ found that for Exelon-treated patients over a 52-week period, behaviors improved so much that the dose could be reduced or the medication discontinued nearly 60% of the time.
       There are many guidelines that apply to pharmacological treatment issues for BPSD. The rational decision process for the use of antipsychotics for BPSD must include the implementation of

Figure 1

nonpharmacologic interventions, consideration of treatment of the underlying disease process, evaluation of alternative medications, and application of a patient-specific risk-to-benefit assessment prior to the prescription of an antipsychotic agent. The Omnicare Guideline for BPSD Medication Management (see Figure 1), published by Omnicare, Inc., focuses on recognition of behavior clusters and recommended pharmacologic interventions. These clusters include aggression/anger, depressive symptoms, insomnia, and frank psychotic symptoms.

Role of the Consultant/Senior Care Pharmacist

       Early screening, diagnosis, and treatment of Alzheimer’s disease yield the best clinical outcomes from the cognitive-enhancing treatments now available and, along with nonpharmacological interventions, provide the basis for rational behavioral treatments for BPSD. Consultant/senior care pharmacists can assist the multidisciplinary team with screening tools, such as the Cognitive Performance Scale of Minimum Data Set (MDS) 2.0 in the nursing home environment as well as the application of the Mini Mental State Examination (MMSE), Clock Draw, and other assessment tools in both the nursing home and community senior care environments. Your pharmacist colleagues can assist the interdisciplinary team with:
• Differential diagnosis to rule out reversible causes of dementia
• Appropriate treatment pathways for Alzheimer’s disease treatment
• Application of a step-wise approach to management of BPSD
• Assistance in determining thoughtful and weighted use of antipsychotics
• Clinical follow up and monitoring of efficacy and side effects
• Routine assessments for dosage reduction and discontinuation of therapy.
       Include the consultant/senior care pharmacist on your behavioral committees and care plan teams, and use his or her expertise during the evaluation process when deciding upon the most appropriate behavioral pharmacological interventions for individual patients with Alzheimer’s disease. With a multidisciplinary approach, the long-term care treatment team can play a large role in restoring and maintaining the quality of life and dignity of our patients.