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About the Author:
Richard G. Stefanacci, DO, MGH, MBA, AGSF, CMD

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Combination Therapy: Optimizing the Treatment of Moderate to Severe Alzheimer’s Disease

According to the Alzheimer’s Association, one in eight people over the age of 65 has Alzheimer’s disease (AD),(1) a condition characterized by impaired functional ability, behavioral problems, and cognitive decline.(2) “The impaired functional ability associated with AD may include problems with eating, grooming, bathing, toileting, and walking,” explains Richard G. Stefanacci, DO, MGH, MBA, AGSF, CMD. “Behavioral problems, such as agitation, irritability, and restlessness, are also common in AD. The cognitive decline experienced by these patients may impact memory, communication, and social interaction.”

Approximately 70% of all nursing home residents have some degree of cognitive impairment.(1) Despite this high prevalence, only about 47% of nursing home residents have received a diagnosis of AD or another dementia.(1) It has been estimated that 58% of patients with AD are first diagnosed in the moderate or severe stage of the disease.(3) “This is why it’s important that all nursing home staff are familiar with identifying the signs and symptoms of AD,” Dr. Stefanacci says. “It’s also important for nursing staff to understand the benefits of all available treatment options so they can manage expectations in AD treatment in themselves, residents, and families.”

Understanding the differences in severity of AD among residents at long-term care facilities can be helpful for caregivers (Figure 1).(2,4) “Although classifying patients appropriately is important,” says Dr. Stefanacci, “it may be more important to simply make the diagnosis of AD. Many patients are not being diagnosed until the disease has progressed substantially.”

Benefits of Therapy

AD is marked by continuous decline, so it can be difficult to determine therapeutic benefits for the disease. “Currently, no therapies cure or reverse the progression of AD,” says Dr. Stefanacci. “As such, providers must aim to improve symptoms, temporarily stabilize symptoms, or slow progression of the disease [Figure 2]. Ideally, the goal is to improve quality of life for patients and formal and informal caregivers.”

Data have shown that AD patients who are untreated decline more rapidly than those who are treated.(5) Other clinical trials of patients with AD indicate that withdrawing and restarting treatment may result in loss of benefits.(5) Currently, there are two classes of drugs that have been approved by the FDA for the treatment of patients with AD: cholinesterase inhibitors and memantine, a N-methyl d-aspartate (NMDA) receptor antagonist. “Cholinesterase inhibitors prevent the breakdown of acetylcholine, a chemical messenger considered to be important for learning and memory,” Dr. Stefanacci explains. “Memantine is an NMDA receptor antagonist that was approved by the FDA as a first-in-class treatment of moderate to severe AD.(6) It focuses on glutamate—a chemical in the brain that is also important for learning and memory.”

When mild AD has been diagnosed, Dr. Stefanacci says that physicians will typically begin patients on a cholinesterase inhibitor to manage symptoms. “However,” he adds, “most patients are being diagnosed in their long-term care facility at a point in the disease in which symptoms are already moderate or severe. For these patients, combination therapy with memantine may be more appropriate. It's also important for formal and informal caregivers to recognize that when memantine is initiated, patients may experience an 'awakening' in which they become more aware of their environment. It's a common occurrence that happens relatively quickly after initiating the medication, but this issue generally resolves over time."

Combination Therapy Improves Behavior

Disruptive behaviors associated with AD can have a negative impact on staff and other residents in long-term care facilities.(7) Agitation or irritability may lead to physical or verbal outbursts, including outbursts during hours when others in long-term care facilities are sleeping.(7) Agitation can also negatively impact caregiving.(7) Managing behavior and sustaining function may promote a safer environment for residents and staff and can also improve the ability to provide care.(7)

One study demonstrated that combining the use of memantine with donepezil can significantly improve and maintain behavior in patients with moderate to severe AD.(8,9) Combination therapy with memantine and donepezil improved and maintained behavior above baseline for 6 months when compared with a combination of placebo and donepezil. “The data available also demonstrated that combining memantine with donepezil led to significant reductions in agitation or aggression and irritability or lability,” Dr. Stefanacci says.

Other data have shown that more patients with moderate to severe AD remained asymptomatic when they were treated with memantine plus donepezil as compared with placebo plus donepezil (Figure 3).(8,9) “In addition to this benefit,” explains Dr. Stefanacci, “patients receiving combination therapy with memantine and donepezil experienced reductions in agitation and aggression as well as improvements in nighttime behavior and appetite or eating.(8,9) This may lead to reductions in stress for caregivers of AD patients.”

Benefits in Function

Declining function in activities of daily living (ADLs) has also been shown to increase dependence on caregivers.(10) “Staffing challenges in long-term care may demand more care with fewer resources,” Dr. Stefanacci says.

In addition to benefits observed with combination therapy consisting of memantine and donepezil in patients with moderate to severe AD with regard to behavior, other research has demonstrated that combining these therapies can result in improved function.(9) Data demonstrated that using memantine and donepezil in combination can result in significantly less decline in performance of ADLs when compared with similar patients who received placebo and donepezil, even after 6 months (P=0.02).(9) “Combination therapy with memantine and donepezil was associated with improvements in ADLs,” says Dr. Stefanacci (Figure 4).(11) “This is important because the demand for provider time in long-term care facilities is significant. Professional caregivers may have more time to care for others in their facility if patients with AD can perform these ADLs.” Additionally, research showed that significantly more patients taking memantine plus donepezil completed the trial when compared with patients taking the combination of placebo and donepezil (P=0.01).(9)

Also, caregivers have reported significantly better functional communication abilities in patients with moderate to severe AD taking memantine and donepezil in combination when compared with patients taking placebo plus donepezil at week 24 (P‹0.01).(9,10) Individuals who received memantine plus donepezil performed significantly better on naming tasks than those taking placebo plus donepezil (P‹0.01).(9,10) Dr. Stefanacci says this is helpful for providers in long-term care facilities “because enhancing patients’ abilities to communicate socially and interact with others may increase connectedness with family members and caregivers.”

Improving Cognition

A third key consideration when managing patients with moderate to severe AD is cognition, and research has shown that memantine plus donepezil can significantly improve cognitive performance when compared with placebo plus donepezil when measured 24 weeks after therapy (P‹0.001).(9) Data show that combining use of memantine and donepezil led to significant benefits in memory, language, and praxis (Figure 5).(12)

According to Dr. Stefanacci, providers in long-term care facilities must seek out the diagnosis of AD and provide treatment early. “Once AD is diagnosed, it’s important to discuss the expectations of patients and their families, friends, and caregivers, and to monitor them for improvements in symptoms after therapies are initiated.”

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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