Two classes of medications have been approved by the FDA to treat symptoms of Alzheimer’s disease (AD): cholinesterase inhibitors and an N-methyl d-aspartate (NMDA) receptor antagonist.(2) Cholinesterase inhibitors were the first medications approved for AD, and they work by preventing the breakdown of acetylcholine, a chemical messenger important for learning and memory.(2) Donepezil,(3) rivastigmine,(4) galantamine,(5) and tacrine(6) are the four FDA-approved cholinesterase inhibitors currently available for the treatment of AD. Memantine,(7) an NMDA receptor antagonist, is believed to work by regulating glutamate activity, a different chemical messenger involved in learning and memory.(2)
Treatment & Management of Patients With Alzheimer’s Disease
“The diagnosis of AD in the long-term care setting has been on the rise,” explains Richard G. Stefanacci, DO, MGH, MBA, AGSF, CMD. “The disease has been associated with excess medical care utilization.”(8) The advent of different treatment options during the past decade has led to advances in patient management and treatment for AD. In 2006, Howard M. Fillit, MD, and a panel of leading experts published recommendations for best practices in the treatment and management of Alzheimer’s disease in the American Journal of Geriatric Pharmacotherapy. These recommendations were developed in an effort to address issues surrounding early diagnosis, treatment, and care management of AD as well as societal and managed care implications.(9) The panel noted that the therapeutic options—used as monotherapy and in combination—have created an expanded role for managing AD in various care settings and at different stages of the disease. An algorithm was created to assist providers in the appropriate utilization of therapy and care management (Figure 1).(9)
The algorithm by Fillit et al recommends using combination therapy with a cholinesterase inhibitor and memantine for patients who progress from mild to moderate AD.(9) "We have data demonstrating the efficacy of combination therapy using donepezil, a cholinesterase inhibitor, together with memantine,”(9) says Dr. Stefanacci. A 6-month trial compared patients who received memantine plus donepezil to those who received placebo plus donepezil. Adding memantine to donepezil improved cognitive performance and resulted in significantly less decline in activities of daily living versus placebo plus donepezil.(10) “The treatment algorithm supports the view that combination therapy confers added benefits over monotherapy,"(9) Dr. Stefanacci adds.
Patients first diagnosed with severe AD should be treated with memantine, according to Fillit et al, but the guidelines also recommend combination therapy with a cholinesterase inhibitor.(9) "If patients progress to the severe stage of the disease while taking a cholinesterase inhibitor, the cholinesterase inhibitor should be continued and memantine should be added if not previously instituted,"(9) says Dr. Stefanacci.
Real World Data Supports Combination Therapy Use
In addition to the recommendations by Fillit et al supporting the use of combination therapy consisting of a cholinesterase inhibitor and memantine in patients with moderate to severe AD, studies continue to emerge that further encourage this treatment strategy. In the September 2008 issue of Alzheimer Disease and Associated Disorders, results from an NIH-sponsored study conducted at the Memory Disorders Unit at Massachusetts General Hospital were published.(1) This study, conducted by Atri et al, included data from 382 patients with AD that were collected over the course of 15 years. “The results from this study provide additional support for the effectiveness of combination therapy for AD patients,” says Dr. Stefanacci.
The objective of the Atri study was to compare the “real world” clinical effectiveness and the long-term clinical trajectory in patients with AD who received no treatment (144 AD patients), a cholinesterase inhibitor alone (122 AD patients), and memantine plus a cholinesterase inhibitor (116 AD patients). The study was conducted between 1990 and 2005 in a prospective manner. Cognitive and functional differences between the three treatment groups were measured.(1) The mean time in the study was 2 years in the no treatment group, 2.2 years in the group receiving a cholinesterase inhibitor alone, and 3.3 years in the group receiving memantine plus a cholinesterase inhibitor.(1)
"Patients in the no treatment group were enrolled from 1990 to 1995, when cholinesterase inhibitors and memantine were not in routine clinical use,"(1) explains Dr. Stefanacci. "Patients receiving a cholinesterase inhibitor alone and those in the combination groups were enrolled after 1997, when widespread clinical use of cholinesterase inhibitors began in the United States. Memantine became available for clinical use in the United States in 2004."(1) On average, patients were enrolled in the Atri study for at least 2 years.(1)
The outcome measures used for this study were the Blessed Dementia Scale (BDS) to assess cognition and the Weintraub Activities of Daily Living (ADL) scale to assess function. The BDS is a brief mental status test administered by a physician to assess cognitive impairment; it collects data on patient information, orientation, memory, and concentration.(1) The Information-Memory-Concentration subscale of the BDS was used in the study. The number of mistakes was recorded; 4 to 10 mistakes indicated mild impairment, 11 to 16 mistakes indicated moderate impairment, and more than 16 mistakes indicated severe impairment.(1) The Weintraub ADL scale is a 31-item questionnaire on both basic and instrumental ADLs. This questionnaire is completed via interviews with spouses or other caregivers. Scores range from 0% (normal) to 100% dependency.(1) Both of these scales were in routine use at the Memory Disorders Unit.(1) All collected data were analyzed using a predictive model to determine probable patient outcomes in cognition and function over a 4-year period. The model used in the study by Atri et al accounted for baseline differences associated with patients in a real-world setting. All patients were evaluated using these scales at the time of entry into the study and at a minimum of 3 additional visits.(1)
Combination Therapy Associated With Sustained Benefits in Cognition & Function
According to the study by Atri et al, patients receiving combination therapy may experience significantly slowed cognitive decline (Figure 2).(1)The data showed that the mean deterioration for an untreated patient was 3 to 4 errors per year. Combination therapy decreased deterioration by 2 errors per year.(1) “The difference of just 1 error per year can make a significant clinical difference,” says Dr. Stefanacci. “It could mean that patients remember their spouse’s name or the time of day they need to take medication. It could also mean that they are able to concentrate on a specific task. Each of these improvements could impact the Alzheimer’s patient and their formal and informal caregivers in a positive way.”(11)
With regard to function, the study by Atri et al demonstrated that patients receiving combination therapy may experience less dependence when compared to therapy with a cholinesterase inhibitor alone and no treatment (Figure 3).(1) “The ability for patients to be less dependent on their formal and informal caregivers may mean patients can be better able to dress themselves, use the phone, or keep their house clean,” Dr. Stefanacci notes.
Assessing the Effect Size
Effect size is a term given to a family of indices that measure the magnitude of a treatment effect. In the book Statistical Power Analysis for the Behavioral Sciences, author Jacob Cohen defined effect sizes as small (d=0.2), medium (d=0.5), or large (d=0.8).(12) In the study by Atri et al, the research team determined Cohen’s d effect size estimates for the BDS for all three treatment groups. The dBDS values for combination therapy consisting of memantine and a cholinesterase inhibitor versus no treatment were statistically significant (P<0.001) for all years in the study, and the values increased across time.(1) The dBDS values for combination therapy versus cholinesterase inhibitor monotherapy were statistically significant (P<0.01) at year 2, with a magnitude of 0.34. The values were also significant (P<0.001) at years 3 and 4, with values of 0.44 and 0.49, respectively (Figure 4).(1)
The study by Atri et al also determined Cohen’s effect size estimates on the ADL score for all patient groups at 1 to 4 years. The dADL values for combination therapy with memantine plus a cholinesterase inhibitor versus no treatment were statistically significant (P<0.05) at year 1, corresponding with a value of 0.32.(1) The values were also significant (P<0.001) at years 2 to 4, with values that increased from 0.48 to 0.67.(1) The dADL values for combination therapy versus cholinesterase inhibit or monotherapy were statistically significant (P<0.001) at years 2 to 4, increasing from 0.46 to 0.73 (Figure 5).(1) “The study by Atri et al really supports the long-term benefits of combination therapy in treating AD with regard to cognition and function,” adds Dr. Stefanacci. “Cognition and function are generally two hallmark areas for caregiver burnout. Managing behavioral issues is another source of caregiver difficulty. The Atri study should give caregivers some sense of comfort that combination therapy may positively impact cognition and function for those with AD. In turn, combination therapy may benefit patient behavior.”
Ensuring Continuity of Treatment
Patients and caregivers should be counseled with regard to “realistic” expectations of pharmacologic treatment for AD.(9) “It’s important to counsel caregivers with regard to expectations of therapy based on the results of clinical trials so that therapies are administered and continued appropriately,” Dr. Stefanacci says. “Although patients receiving therapy are expected to experience symptomatic decline over time, clinical trials suggest that this decline is delayed with the use of such therapy. Therapies for AD should be empirically continued unless contraindicated or if there is clear evidence that such therapies are no longer effective.”(9)
Due to the complexity of medical and care management issues, geriatric care management and counseling should be provided to all patients with a diagnosis of AD and to their formal and informal caregivers.(9) “It should be noted that AD medications are sometimes stopped when patients move from a nursing facility to a hospital for acute care,” says Dr. Stefanacci. “Often, these patients are never put back on their AD medications. This can be problematic because it may exacerbate functional, cognitive, and behavioral problems, possibly complicating the acute condition being treated. Thus, AD medications should be continued during illness or hospitalization.”(9)
Dr. Stefanacci says that clinicians need to work aggressively with formal and informal caregivers. "Physicians, especially those in primary care, other provider-based medical management programs, and public service organizations. such as the Alzheimer’s Association can provide needed counseling for caregivers.(8) In addition, collaborative efforts with nurses and other caregivers are important because they’re on the front lines. By informing all caregivers of the benefits of combination therapy as well as the importance of continuity of treatment, physicians may improve quality of life for patients and caregivers battling this complex disease."
Richard G. Stefanacci, DO, MGH, MBA, AGSF, CMD has indicated to Physician’s Weekly that he has been on the speaker bureau for Pfizer, Ortho McNeil, Abbott, GlaxoSmithKline, AstraZeneca, Forest Laboratories, Merck, Daiichi Sankyo, Par, Eisai, and Schering Plough. He has also served as a consultant for Celegene, New Courtland Elder Services, Baxter, Eisai, Pfizer, Sanofi-Aventis, Sepracor, Amgen, Merck, Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, Novartis, and Wyeth. He has been on the advisory board for Pfizer, Eisai, Janssen, Solvay, Takeda, Genentech, Myrida, and Novo Nordisk. He has received grants from the American Society of Consultant Pharmacists, Sanofi-Aventis, Amgen, Merck, and Forest.
Prescribing Information
Indications
NAMENDA® (memantine HCl) is indicated for the treatment of moderate to severe Alzheimer’s disease.
NAMENDA® is contraindicated in patients with known hypersensitivity to memantine HCI or any excipients used in the formulation. The most common adverse events reported with NAMENDA vs placebo (=5% and higher than placebo) were dizziness, confusion, headache, and constipation. In patients with severe renal impairment, the dosage should be reduced.
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