Submission of Evidence on Memantine for the Scottish Medicines Consortium

1 Introduction

Alzheimer Scotland is a national charity representing the interests of Scotland's estimated 62,000 people with dementia and their carers. We provide services and actively campaign to help people with dementia, their families and carers. This document represents the viewpoint of Alzheimer Scotland on memantine for consideration by the Scottish Medicines Consortium.

Alzheimer's disease is a progressive illness, affecting memory, understanding and behaviour. People with Alzheimer's disease gradually lose their ability to carry out the activities of daily living, such as shopping, handling money, personal care and cooking. Eventually even basic activities, such as dressing and going to the toilet become impossible without help. Memantine is the first drug to be licensed for the treatment of moderately severe to severe Alzheimer's disease. It has been marketed in Germany by Merz Pharmaceuticals for over a decade for use in Parkinson's disease and other neurodegenerative diseases. It was licensed in May 2002 by the European Union for use in Alzheimer's disease and was launched in the United Kingdom by Lundbeck Ltd in October 2002.

This report firstly details previous approved treatments for Alzheimer's disease and the associated problems that prevailed with postcode prescribing. Secondly, the potential benefits of memantine are discussed. Finally, the findings of a recent survey on memantine carried out by Alzheimer Scotland are presented.

2 Postcode Prescribing Concerns

The first drug for mild to moderately severe Alzheimer's disease, donepezil (Aricept), was licensed in the United Kingdom in April 1997. There are now two more licensed treatments for this category of Alzheimer's disease: rivastigmine (Exelon) and galantamine (Reminyl). These drugs are called cholinesterase inhibitors and can help to improve or stabilise the symptoms of Alzheimer's disease in many, but not all, people with the illness who are prescribed them.

As soon as donepezil was licensed, it was difficult for many people with Alzheimer's disease to gain access to the cholinesterase inhibitor drugs that could help them. This was the result of many health boards awaiting better evidence of efficacy. Yet, as the evidence became available, some still failed to fund treatment. This resulted in a 'postcode lottery', which meant that in some areas treatment was available, in some it was limited and in some it was impossible to obtain unless on a private prescription.

In January 2001, the National Institute for Clinical Excellence in England and Wales recommended that the NHS fund treatment for Alzheimer's disease drugs. In April 2001, the Health Technology Board for Scotland (HTBS) issued its own recommendations, following the NICE guidance, but amending treatment protocols to suit Scotland.

Every year since 1997, Alzheimer Scotland has renewed its campaign against postcode prescribing. In 2001, a comprehensive survey of health boards Postcode Prescribing Persists [1] was conducted in order to find out how the availability of treatment for Alzheimer's disease had changed, six months on from the NICE report and three months after the HTBS recommendations. A summary of the results of this survey is shown below.

For people with mild to moderate Alzheimer's disease hoping to receive drug treatment, there remained a postcode lottery.

• People living in the areas with better provision, such as Ayrshire and Arran or Lothian, were between five and twelve times more likely to receive treatment than people in the areas with the worst provision, which were Grampian, Tayside, Highland and Orkney.
• Provision in a further six areas (Argyll & Clyde, Borders, Dumfries & Galloway, Fife, Forth Valley, Greater Glasgow) was well below the level we estimated was needed.

In 2003, another survey of Health Boards[2] was carried out to investigate how the situation has changed since 2001, and also to garner policies on the prescription of memantine and estimates on when it would be made available if a positive recommendation is made by the SMC in August 2003. A summary of the results of this survey is shown below.

• A postcode lottery remains. A person living in Argyll & Clyde who is in the early stages of Alzheimer's disease is five times more likely than a person living in Glasgow to receive drug treatment with cholinesterase inhibitors. The size of the drug budgets varies even more - the spending in Argyll & Clyde is nearly eight times that of Ayrshire & Arran.
• Whilst there are no reported waiting lists for receipt of the treatments, there are clearly delays in receiving the assessment necessary for treatment to commence. It is positive that most boards reported relatively short waiting times for appointments, although clearly a wait of four months (in Ayrshire & Arran) is too long. Several health boards reported problems due to gaps in staffing, with others foreseeing problems in the future as prescription demand rises.
• Whilst acknowledging the problems that remain, progress has been made compared to the survey we conducted in 2001. Then, there were four health board areas where less than 10% of those who could benefit from the treatment were receiving the drugs, whereas now no health board is falling below 11%. However, the relative performance of Ayrshire & Arran is disappointing: whereas in 2001 it was one of the better areas, it now appears to be one of the worst. In terms of improvement, it is positive that Grampian has increased its drugs budget by ten times, and that Argyll & Clyde has progressed from treating around 12% to over 55% of those people with Alzheimer's disease we judge able to benefit from the drug treatments.
• With regard to memantine, most areas seem cautious, not only about the cost of the drug, but also the implications for staff time and other resources.

3 Potential Benefits of Memantine

Statistics of people with moderate to severe Alzheimer's disease

The current number of people with dementia in Scotland is 62,000. Approximately 55% of people with dementia have Alzheimer's disease[3], which translates to 33,550 people. 30% of these are estimated to have mild Alzheimer's disease , 42% are estimated to have moderate Alzheimer's disease, and 28% are estimated to have severe Alzheimer's disease. Therefore, a total of 70% of people with Alzheimer's disease are estimated to have moderate to severe Alzheimer's disease, which translates to 23,485 people.

4 Research on memantine

Memantine works differently to the cholinesterase inhibitor drugs. It blocks the activity of glutamate, which excites neurons in the brain. When neurons are overstimulated, an influx of calcium occurs, which is toxic to neurons. The neurons that respond to glutamate are involved in learning and memory so by blocking this overstimulation, the damage to brain cells is lessened. Thus, memantine is not claimed to be a cure for Alzheimer's disease. It treats only the symptoms, and there is no evidence that it could halt or reverse the process of cell damage that causes Alzheimer's disease.

There have been many studies investigating the use of memantine[4]. These mainly show that it will not help everyone who tries it. One study [5] showed that 73% of people taking memantine benefited, yet in the same study, around 45% of patients on the placebo also benefited. The benefits were in practical matters such as getting up, washing, getting dressed, and going to the toilet. People who were helped by the drug needed less help from carers. The drug also improved scores in tests of cognition. Another study [6] showed that both the group treated with memantine and those on the placebo got worse over six months, but those on memantine declined less.

The results of a more recent study [7] showed that caregiving time was less for the caregivers of people on memantine than for the caregivers of the people receiving a placebo treatment. A high percentage of people experienced adverse events during the study (84% with memantine and 87% with the placebo), which is generally expected when the people involved have a moderate to severe illness. However, these events were mild to moderate in severity and were either not related or unlikely to be related to the study medication. The incidence rates for the frequently reported adverse events in the memantine group were no more than 2% higher than in the placebo group.

Another study [8] conducted in Sweden concluded that carers' hours were significantly reduced by 51.5 hours per month, with the time to institutionalisation also significantly extended in the memantine group, as opposed to the placebo group. It was also found that total costs from a societal perspective were lower in the memantine group and that the main differences between the two groups were total caregiver costs and direct nonmedical costs, both of which favoured memantine treatment. Direct medical costs were higher in the memantine group, which was mainly due to the cost of memantine. It was concluded that treating people with moderate to severe Alzheimer's disease with memantine is cost saving from a societal perspective.

These results are viewed as being encouraging, as memantine could be a beneficial treatment for two groups of people with Alzheimer's disease - those who are being cared for in their own homes and who have become highly dependent on their family caregivers and those who are in care homes and are dependent on care staff.

5 Alzheimer Scotland Findings

Survey Findings

In order to compile opinions on memantine from people with Alzheimer's disease and their carers, Alzheimer Scotland constructed a questionnaire regarding the following areas:

• the main difficulties of caring for someone with Alzheimer's disease
• the predicted benefits of memantine
• whether NHS Scotland should prescribe memantine
• whether the respondents knew anyone who has been prescribed memantine and if so, what the benefits were.
• A total of forty-four questionnaires were sent to a combination of Alzheimer Scotland services, branches, carer education projects and carer panels. A total of twelve responses were received. Eight completed the questionnaire in small discussion groups:

1. Banff Carer Support Group
2. Drop in users to Aberdeen City Services office
3. Dumbarton Carers Group
4. Falkirk Carer Support Group
5. Glasgow Carers Panel
6. Ross-shire services
7. Skye and Lochalsh Services
8. West Stirlingshire Support Group & Stirling Clackmannanshire Rural Support Group.

General comments were received from:
9. Highland Carer Resource Project [9]
10. Inverclyde Project
11. WISDOM Project (South Ayrshire)

When analysing the questionnaires, nine responses (all questionnaire respondents and comments from Highland Carer Resource Project) were taken into account. The two sets of general comments were excluded from the analysis. The results that will be discussed in this report are the main difficulties of caring for someone with moderately severe to severe Alzheimer's disease and the predicted benefits of prescribing memantine to someone with Alzheimer's disease.

The responses[10] obtained with regard to the main difficulties of caring for someone with moderately severe to severe Alzheimer's disease are made clearer when they are divided into two sections. The first concerned the impact of caring for someone moderately severe to severe Alzheimer's disease upon the carer (see table one), and the second described some specific symptoms of moderately severe to severe Alzheimer's disease that carers find difficult (see table two).

Overall, the results show the huge impact on the carer's life that caring for someone with moderately severe to severe Alzheimer's disease has. Areas affected are managing their own life and health, through to the emotional and financial implications that exist. Tiredness and fatigue were cited most frequently. Rather than commenting that not enough external help was available, more comments were made regarding the quality of the external care provided and the stress it caused when it did not take into consideration the wishes of the person with Alzheimer's disease and their carer.

The symptoms of moderately severe to severe Alzheimer's disease that carers found most difficult were varied and ranged from behavioural and memory problems through to difficulties managing personal care and problems at mealtimes. The symptoms that were mentioned most were agitation / inability to settle, wandering and incontinence.

The responses to the question regarding the predicted benefits of prescribing memantine to someone with moderately severe to severe Alzheimer's disease are separated into the benefits of prescribing memantine to people with Alzheimer's disease and to their carers (see table three).

The predicted benefits of prescribing memantine to people with Alzheimer's disease were twofold. It was mainly predicted that it would give the person with Alzheimer's disease a better quality of life through, for example controlling and slowing the progression of the Alzheimer's disease and giving the person with Alzheimer's disease the ability to continue to do things for themselves, thus preserving some degree of independence. Secondly, there were predicted benefits for the carer, which were mainly less stress and an ability to cope for longer. It was also noted that any general improvements in the person with Alzheimer's disease would benefit the carer.

Impact on carer's health of caring for someone with Alzheimer's disease

As can be seen from table one, caring for someone with Alzheimer's disease can have a significant impact on the health of the carer. The following points provide a summary on carer stress and dementia[11] .
[bullets]Carers of people with dementia suffer from high stress levels and, compared with non-caregivers, are 50% more likely to take prescribed medication, visit their GP and report higher levels of stress and physical symptoms[12] .
The most dominant causes of stress in carers are psychiatric symptoms and behavioural disturbances in the person with dementia (which may be even more common in younger people with dementia), and not the degree of cognitive impairment or difficulties with activities of daily living.
Other predictors of high stress levels include: the amount of formal and informal care available, the carer's physical and mental state and their personality and coping style. The emotional relationship between the cared-for person and the carer is also seen as a key factor when the carer is faced with difficulties.
A diagnosis disclosed to the carer and not the person with dementia often increases carer stress.
Carers often feel unheard by health and social care professionals.
There is a need to provide more practical support for carers who have to work, as well as counselling and education to assist relieving the emotional stress of care giving.
There is an increased risk of depression in carers of people with dementia, particularly for women, those over 65, co-resident or next of kin to the person cared for; prevalence is estimated at 30-50%.
Spouses and children had significantly higher odds of high depression scores than other caregivers.
Studies have also found that other unusual features observed in carers of people with dementia include the high use of psychotropic medication, poor self-care and physical abnormalities such as elevated blood pressure, high plasma lipid levels and impaired immune function. [endbullets]

6 Summary and Conclusions

This report has put forward three main bodies of evidence, that are extremely important for the Scottish Medicines Consortium to take into account when considering memantine for recommendation. The first provided a background to the postcode prescribing that occurred with the cholinesterase inhibitor drugs. We do not want to see a repetition of this situation with memantine if it is recommended by the SMC.

Secondly, evidence from research studies on the potential benefits of memantine was provided. This generally showed that memantine could be beneficial for people with Alzheimer's disease who are being cared for in their own homes and who have become highly dependent on their family caregivers and also those who are in care homes and are dependent on care staff. In addition a study by Wimo et al (2003) [8] was described, which concluded that memantine is cost saving from a societal perspective.

Finally, results from a recent survey on memantine conducted by Alzheimer Scotland were reported. This illustrated the huge impact that caring for someone with Alzheimer's disease has on the carer's health, emotions, finances and management of their own life. A large variation of symptoms of Alzheimer's disease were described that carers find difficult to cope with. Additionally, there were many predicted benefits of memantine, which centred on giving people with Alzheimer's disease a better quality of life.

Overall, the evidence presented in this report regarding memantine is compelling. Three conclusions are made:

It is the view of Alzheimer Scotland that memantine should be recommended by the Scottish Medicines Consortium. If it is, then we believe that there should be a simple protocol put in place to monitor people with Alzheimer's disease taking memantine, in order to ensure that they benefit from the treatment.

We do recognise that memantine is not likely to benefit all patients and that this is not a treatment that reverses the course of the illness.

The benefits of memantine are extremely important from the perspective of people with Alzheimer's disease and their carers. In addition, we wish to avoid the anguish of carers who do not get the opportunity to see if the drug will benefit their relative.

[1]Alzheimer Scotland (2001) Postcode Prescribing Persists.
[2] Alzheimer Scotland (2003) Postcode Prescribing Still Persists.
[3] Medical Research Council (1998) Cognitive function and dementia in six areas of England and Wales. Psychological Medicine, 28, 319-335.
[4] See Alzheimer Scotland (2002). Drug treatment for Alzheimer's disease - Ebixa or memantine. Available from http://www.alzscot.org/info/ebixa.html(or here)
[5] Winblad B., Poritis N. (1999) Memantine in severe dementia: Results of the M-Best Study. International Journal of Geriatric. Psychiatry 14, 135 -146.
[6] Reisberg B., Ferris S.H., Sahin K., Windscheif U., Möbius H.J. (2000) Results of a placebo-controlled 6-month trial with memantine in moderate to severe Alzheimer´s disease (AD). Neurobiol. Aging 21, 275.
[7] Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobias H.J. for the Memantine Study Group. (2003) A randomised, placebo-controlled study of memantine, an uncompetitive NMDA antagonist, in patients with moderate to severe Alzheimer's disease. New England Journal of Medicine. 348, 1333-41.
[8] Wimo A, Winblad B, Stoffler A, Wirth YM and Mobias H.J. (2003) Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer's disease. Pharmacoeconomics 21(5): 1: 1170-7690.
[9] This covered four out of the seven questions asked in the questionnaire, therefore was analysed along with the questionnaire responses.
[10] Information from eight respondents is used here. Respondent 9 omitted answering this question.
[11] Alzheimer Scotland (2003) Signposts to support: understanding the special needs of carers of people with dementia. See http://www.alzscot.org/policy/signpoststosupport.html (or here)
[12] Burns A & Rabbins P (2000) Carer burden in dementia. International Journal of Geriatric Psychiatry, July; 15 Suppl 1:S9-13