R. W. Jones
INTRODUCTION
The cholinergic hypothesis, which states that one of the primary abnormalities in Alzheimer’s disease (AD) is due to a deficiency in acetylcholine, has led to a number of therapeutic strategies. The most successful has been the development of cholinesterase inhibitors.
Four cholinesterase inhibitors – tacrine, donepezil, rivastigmine and galantamine – have been licensed for the treatment of mild to moderate AD. In 1993, tacrine became the first agent approved specifically for treating the cognitive symptoms of AD. Tacrine, an aminoacridine compound, became widely used in many countries including the USA, Sweden and France but was never marketed in the UK. It needed to be taken three or four times a day, was often poorly tolerated and caused a specific reversible hepatotoxicity.
When donepezil became available in 1997 with its better tolerability and once daily dosing, not surprisingly it rapidly replaced tacrine as the drug of choice. Rivastigmine (since 1998) and galantamine (since 2000) are now also widely available, thus offering further options both to prescribers and to patients and carers.
A fifth drug, memantine, has been licensed since 2002 and is approved in Europe and the US for moderate to severe AD. In contrast to the cholinesterase inhibitors, memantine acts on another neurotransmitter glutamate and is a moderate affinity, uncompetitive antagonist at the N-methyl-D-aspartate receptor.
There have been no direct head-to-head comparisons either of tacrine with other cholinesterase inhibitors or of memantine with any of the cholinesterase inhibitors; neither tacrine nor memantine will therefore be discussed further in this chapter.
Donepezil is a piperidine-based reversible inhibitor of acetylcholinesterase that is highly selective for acetylcholinesterase with much less activity against butyrylcholinesterase. Red blood cell acetylcholinesterase inhibition at steady state was 64% with 5 mg/day and 77%
with 10 mg/day. Inhibition up to 90% has been reported during long-term treatment with 10 mg/day [1]. Absorption is complete and neither food nor time of administration (morn- ing or evening) influences the rate or extent of absorption. Peak plasma concentrations are reached after 3–4 h and steady state plasma levels after about 15 days. The effective dose range is 5–10 mg beginning with a single daily tablet of 5 mg and usually increasing after a minimum of 1 month to 10 mg according to efficacy and tolerability. Most patients are main- tained on the maximum recommended daily dose of 10 mg [2, 3].
Rivastigmine is a centrally selective carbamate inhibitor of acetyl and butyryl- cholinesterase. It forms a carbamylated complex with the enzyme and inactivates it for
Roy W. Jones, BSc (Hons), MBBS, Dip Pharm Med, FRCP, FFPM, Professor of Clinical Gerontology and Director, The Research Institute for the Care of the Elderly, St Martin’s Hospital, Bath and School for Health, University of Bath, Bath, UK
©Atlas Medical Publishing Ltd 2007
about 10 h (‘pseudo-irreversible’ inhibition) despite a short plasma half-life of 1–2 h. A sin- gle 3 mg oral dose produces 30–40% inhibition of central acetylcholinesterase but minimal inhibition in the red cell or plasma. In contrast, it inhibits both acetyl and butyryl- cholinesterase in the cerebrospinal fluid (CSF) to a similar extent [1]. Absorption is reported as rapid and complete, yet bioavailability increases with dose. Administration with food slows absorption and increases the area under the concentration–time curve by about 30%.
Rivastigmine should be administered with food twice daily commencing at 1.5 mg b.d. (not a therapeutic dose) and increasing at a minimum of 2-weekly intervals to achieve the effec- tive dose range of 3–6 mg b.d.
Galantamine is a phenanthrene alkaloid that is a reversible, competitive acetyl- cholinesterase inhibitor. Thirty–sixty percent inhibition of red blood acetylcholinesterase is obtained 30–45 min after oral galantamine [1]. Activity against acetylcholinesterase is more than 50-fold greater than inhibition of butyrylcholinesterase. In addition, galantamine is also an allosteric modulator of neuronal nicotinic receptors, a property that has been demon- strated in human nicotinic receptors expressed in cell lines [4]. The bioavailability of galan- tamine after oral administration is 85% with a plasma elimination half-life of about 6 h. One of the metabolites of galantamine is more active as an acetylcholinesterase inhibitor than the parent compound [1]. The relatively short half-life of galantamine requires twice-daily administration. Treatment should begin with 4 mg twice daily for 4 weeks following which the dose is increased to a clinically effective dose of 8 mg b.d.; the dose can be increased to 12 mg twice daily after a further 4 weeks. It is recommended that adequate fluid intake is ensured during treatment. More recently, a once-daily prolonged release capsule formula- tion of galantamine (8 mg, 16 mg and 24 mg) has been marketed.
There are numerous studies comparing each compound – donepezil, rivastigmine and galantamine – with placebo. Comparison of the relative efficacy and tolerability of the three compounds across clinical trials is inappropriate because of the different populations stud- ied (with differing factors such as disease severity, comorbid conditions and concomitant medication use), differences in outcome measures, differences in safety evaluations and dif- ferent dosing regimes [2, 5]. Randomized clinical trials that directly compare one agent with another are the best way of making appropriate comparisons [5]. Ideally these trials should also be conducted using standard double-blind methodology although this can be problem- atic when the drugs have different frequencies of dosing and different dosing regimes. This may necessitate the use of double-dummy techniques or reformulation (e.g. into capsules) that may increase both the frequency and the number of capsules/tablets to be taken. This may increase the artificiality of the clinical trial situation in contrast to the normal situation in clinical practice where a simpler dose titration or dose frequency may offer a potential practical advantage.
Nevertheless, four randomized clinical trials looking at head-to-head comparisons have now been published: two studies compare donepezil and rivastigmine (one sponsored by Eisai/Pfizer, makers of donepezil, and one by Novartis, makers of rivastigmine) and two studies compare donepezil and galantamine (again one sponsored by Eisai/Pfizer and one sponsored by Janssen/Shire, makers of galantamine). There are no published direct com- parisons between rivastigmine and galantamine nor between donepezil and the recently marketed prolonged release galantamine.
DONEPEZIL VS. RIVASTIGMINE: 12-WEEK STUDY [6]
The first published head-to-head study was a 12-week multinational comparison assessing the tolerability, compliance and cognitive effects of the recommended doses of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily). Patients who had previously received either drug were excluded. Patients receiving donepezil commenced on 5 mg tablets once daily for 28 days and then 10 mg tablets once daily. Those receiving
rivastigmine initially received 1.5 mg capsules twice daily with food. At 14-day intervals, the patients were assessed and the dosages increased to 3 mg (day 14), 4.5 mg (day 28) and finally to a maximum of 6 mg (day 42) twice daily according to tolerability. In order to assess satisfaction and ease of use with two treatments that differ in terms of dosing frequency and dose escalation schedules, the medication was given open-label and dosage adjustments based on tolerability (down and up) were allowed throughout the study.
Nineteen sites in the UK, South Africa and Switzerland recruited patients with mild-to- moderate probable or possible AD (Mini-mental State Examination [MMSE], 10–26 inclu- sive). One hundred and twelve patients were randomized (1:1 ratio) using a stratified randomization scheme based on centre and disease severity split into mild (MMSE 21–26 inclusive) or moderate (MMSE 10–20 inclusive) categories. One subject received no study medication and the results were therefore presented for 111 patients (56 receiving donepezil, 55 receiving rivastigmine).
OUTCOME MEASURES
Although not specifically stated as the primary outcome measure, the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog) was the only measure administered by independent raters that were blinded to study treatment and outcome. The MMSE was a secondary outcome measure carried out at screening, baseline and at weeks 4 and 12 by clinicians who did have knowledge of the assigned medication.
Tolerability was assessed by comparing treatment groups with respect to adverse event (AE) monitoring together with other factors such as laboratory test abnormalities, electrocardiography (ECG) findings and compliance with study medication.
Physicians and caregivers rated the ease of use and their general satisfaction with the dosing frequency and titration of the assigned treatment by completing Likert-type ques- tionnaires at weeks 4 and 12. These were developed by the Clinical and Outcomes Research
Physician satisfaction/ease of use questionnaire*
1. Ease of medication use by patient and caregiver 2. Satisfaction with dosing frequency
3. Satisfaction with titration schedule to achieve clinically effective dose
4. Frequency of patient monitoring outside scheduled visits for side-effects or medication queries 5. Overall convenience of medication
6. Overall satisfaction with medication Caregiver satisfaction/ease of use questionnaire**
1. Ease of following directions of use
2. Ease of ensuring correct dose given to patient each day
3. Satisfaction with dosing frequency (number of times medication taken daily) 4. Satisfaction with patient tolerability of medication
5. Frequency of doctor contact regarding directions of use 6. Frequency of doctor contact regarding side-effects 7. Overall convenience of medication
8. Overall satisfaction with medication
*All questions scored 1–5 giving a total score range of 6–30. Lower scores indicate greater satisfaction/ease of use.
**All questions scored 1–5 giving a total score range of 8–40. Lower scores indicate greater satisfaction/ease of use.
Table 3.1 Satisfaction/ease of use questionnaires
Group at Pfizer and Eisai in conjunction with an external consultant, Dr Jean Endicott of Columbia University, New York (Table 3.1) [6].
STATISTICAL ANALYSIS
An analysis of covariance model was used for estimating and testing treatment effects. Both observed cases (OC) and last observation carried forward (LOCF) analyses were carried out for the intention-to-treat population (ITT). The publication only describes the OC analysis because of the potential for bias as a result of the large differences in discontinuation rates between the two drugs.
RESULTS
Fifty (89.3%) patients in the donepezil group completed the study compared with 38 (69.1%;
P!0.009) in the rivastigmine group. In the donepezil group 10.7% and in the rivastigmine group 21.8% discontinued because of AEs. At the last study visit 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug. In addition, 17.9% of donepezil- and 34.5% of rivastigmine-treated patients required a dose reduction or temporary discontinuation of study drug. Bradycardia was experienced by 2 donepezil- and 3 rivastigmine-treated patients respectively.
Both groups demonstrated similar improvements on the ADAS-Cog at both weeks 4 and 12. The mean change from baseline in MMSE total scores showed a similar result to the ADAS-Cog.
Physicians and caregivers both reported significantly better satisfaction/ease of use with donepezil in comparison to rivastigmine.
CONCLUSION AND COMMENT
This study using the recommended dosing schedules demonstrated that donepezil was bet- ter tolerated than rivastigmine with fewer discontinuations due to AEs. Both agents appeared to improve cognition to a similar extent.
The data on physician and caregiver satisfaction/ease of use must be interpreted cau- tiously since it relied on a scale that appears to have been developed specifically for the study by Eisai/Pfizer working with an external consultant.
It is generally accepted, based on the pivotal double-blind placebo-controlled studies with the two drugs and on everyday clinical experience (e.g. data submitted in 2005–2006 to the National Institute for Health and Clinical Excellence [NICE] in the UK), that donepezil is bet- ter tolerated than rivastigmine and that more patients can tolerate the maximum recom- mended dose of donepezil than rivastigmine. In this study, the doses of the two drugs were increased using the minimum interval specified in the product labelling and it is possible that slower titration with either drug might have improved tolerability and reduced withdrawal.
RIVASTIGMINE VS. DONEPEZIL: 2-YEAR STUDY [7]
This is the most recently published comparison reporting a large 2-year multinational double-blind randomized controlled study designed to evaluate the efficacy and tolerability of rivastigmine and donepezil. Ninety-four centres in Australia, Canada, France, Germany, Italy, Spain and the UK recruited patients with moderate to moderately-severe AD (MMSE 10–20 inclusive). Although the paper states that the study included probable AD only (NINCDS-ADRDA criteria) [8], subjects with symptoms suggestive of concomitant Lewy body disease were also allowed to enter. A diagnosis of probable AD requires the exclusion, as far as possible, of causes of dementia other than AD so there is some uncertainty about
the nature of the subjects and the rigour with which the diagnosis of probable AD was applied. Nine hundred and ninety-eight patients were randomized in a 1:1 ratio; 994 actu- ally received drug therapy (495 received rivastigmine and 499 received donepezil).
There was a 16-week dose titration period with increases in the rivastigmine dose every 4 weeks beginning at 3 mg/day, increasing in 3 mg steps to a maximum dose of 12 mg/day after 12 weeks (tolerability permitting). It is not stated how the dose was administered but presumably this was as capsules on a twice-daily basis with food as recommended in the product labelling. In order to maintain blinding, donepezil was also administered as cap- sules (together with placebo capsules) commencing at 5 mg/day for weeks 1–4 and weeks 5–8 increasing to 10 mg/day for weeks 9–16. It is not stated how donepezil, which is mar- keted as a tablet, was reformulated into the capsules.
OUTCOME MEASURES
The primary efficacy measure was the Severe Impairment Battery (SIB), which assesses cog- nitive function in severely demented patients. This is an unusual choice for a study involv- ing people with a starting MMSE score of up to 20, but was selected partly because of the intended duration of the study.
Secondary outcome measures included the Global Deterioration Scale (GDS), the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale (ADCS-ADL) although the version for more severely impaired subjects does not appear to have been used, the MMSE and the Neuropsychiatric Inventory (NPI) to assess behavioural problems.
Safety and tolerability assessments included monitoring and recording AEs and regular measurements of vital signs.
A single blood sample at screening was taken from a subpopulation who consented to phar- macogenetic evaluation. About one-third (n!340) of subjects agreed to this, which allowed some secondary, exploratory analyses to be carried out. The objective was to identify genetic factors related to AD that might predict treatment response with rivastigmine or donepezil, or a subject’s relative susceptibility to drug–drug interactions or serious side-effects.
STATISTICAL ANALYSIS
The main efficacy analyses were based on mean change from baseline at 104 weeks in an ITT population, defined as all randomized patients who received study medication and from whom at least one efficacy measurement was obtained on treatment using the LOCF.
An evaluable patient (EP) population was also assessed for those who received at least 16 weeks study medication with the LOCF. Finally an OC population was analysed. As for the previous study, an analysis of covariance model (ANCOVA) was used in the analyses.
Changes from baseline at 104 weeks were assessed for the primary outcome measure (the SIB) and all secondary efficacy variables (GDS, ADCS-ADL, MMSE and NPI). Additional secondary analyses on the SIB, NPI and ADCS-ADL were performed on patients with dif- ferent baseline severities, gender, age and vascular risk factor profiles.
RESULTS
Overall, 57.9% of patients completed the study, 52.7% (261/498) on rivastigmine but 63.5%
(317/495) on donepezil. Premature discontinuations during the 16-week titration period were 18.8% for the rivastigmine group in comparison with 9.2% for the donepezil group.
During the 88-week maintenance phase of the study, discontinuations on rivastigmine were 28.5% compared with 27.3% for donepezil. The most frequent reasons for premature dis- continuation were AEs in 128 (25.9%) on rivastigmine (14.1% in the titration phase and 17.9% in the maintenance phase) and 80 (16.0%) on donepezil (7.0% in the titration phase
and 14.1% in the maintenance phase). Consent was withdrawn in a further 34 (7.5%) on rivastigmine compared with 22 (4.6%) on donepezil whilst other reasons for discontinuation (abnormal laboratory values, unsatisfactory therapeutic effect, protocol violation, loss to follow-up, administrative problems and death) were similar for the two drugs.
More rivastigmine- than donepezil-treated patients reported ‘any AE’ during the titra- tion phase (82.0% and 64.7%, respectively). The higher rate for rivastigmine appeared to be driven by an increased rate, relative to donepezil, of nausea (32.9% vs. 15.2%) and vomiting (27.9% vs. 5.8%). In the maintenance phase, AE rates were similar for the two groups when reported as totals for ‘any AE reported’ but there was still a much higher incidence with rivastigmine of those AEs that appeared in at least 5% of subjects within any treatment group (titration or maintenance phase). In particular, 12.9% of subjects on rivastigmine reported nausea and 15.3% vomiting in the maintenance phase, whereas the comparative figures for donepezil were 5.3% and 4.4%.
EFFICACY
At the end of 2 years’ treatment, the mean daily dose for each drug was 9.4 mg (indicating that more patients were on the maximum recommended dose of 10 mg for donepezil than the maximum recommended dose of 12 mg for rivastigmine). The main efficacy data pre- sented in the publication is for the ITT-LOCF population which showed no statistically sig- nificant difference between the two drugs on measures of cognition (SIB, MMSE) or behaviour (NPI). Rivastigmine showed superior efficacy over donepezil on the ADCS-ADL and greater efficacy on the GDS. However, these differences were not maintained in the non-ITT-LOCF populations (EP and OC populations).
The published abstract within the paper suggests that in some of the secondary sub- group analyses, AD patients who had genotypes for full expression of the butyryl- cholinesterase enzyme (n!226/340), who were "75 years of age (n!362/994) or who had symptoms suggestive of concomitant Lewy body disease (n!49/994) showed significantly greater benefits from rivastigmine treatment. These data are not fully presented in the paper which again relies on the ITT-LOCF data; in addition, the data in the paper suggest that only 40 subjects were thought to have probable concomitant Lewy body dementia (DLB) in contrast to the 49 mentioned in the abstract but not elsewhere in the publication.
CONCLUSION AND COMMENT
The abstract of the paper concludes that cholinesterase inhibitor treatment may offer con- tinued therapeutic benefit for up to 2 years in patients with moderate AD. It goes on to state that although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in ADL and global functioning. It also reports the subanalyses that are mentioned above. These conclusions are misleading.
The major flaw in this study is the considerably greater number of dropouts on rivastig- mine in comparison with those on donepezil (47.3% vs. 36.5%) such that only 261 subjects completed the study on rivastigmine in comparison with 317 on donepezil. Many of these withdrawals were due to AEs and occurred during the early (titration) phase of a study that lasted 2 years. Under these circumstances the ITT-LOCF analysis would favour rivastig- mine because the natural course of AD is a steady decline. This is confirmed by the fact that the statistical significance of these findings disappears when the non-ITT-LOCF analysis is reported. Although the authors do discuss this point in their discussion they still concen- trate on their erroneous conclusions in the abstract. It is noteworthy that the previous donepezil–rivastigmine comparison described above used an OC analysis rather than an ITT approach because of the same problem (a higher dropout rate on rivastigmine), even though the study was considerably shorter.