Cholinesterase inhibitors

Timing of treatment – At diagnosis or delayed start?

Cholinesterase inhibitors are licensed for the treatment of Alzheimer’s disease. An important question is ‘When should a patient with AD start a ChEI?’.

There are two lines of evidence supporting early prescription at the time of diagnosis. First, patients with mild AD derive the same overall global clinical benefit from ChEIs as those with moderate AD, but the benefit in terms of performance on cognitive scales is smaller in those with mild AD than in those with moderate AD. Second, a delay in starting a ChEI might possibly adversely affect the course of the disease. In clinical trials, patients who were initially assigned to the placebo group and then switched to taking a ChEI during open label extensions showed an improvement as expected, but they did not “catch up” with the group that had received a ChEI from the beginning of the trial. This could suggest that ChEIs may provide greater benefit if started as soon as dementia is diagnosed, rather than waiting. It is also suggests that ChEIs might reduce disease progression. If true, this would carry the implication that ChEIs should not be discontinued. However, it is likely that this observation is biased because of missing observations from patients who took the active drug in the randomised part of the study but did badly and so elected not to go onto ‘open label’ drug. In other words, the group which continued open-label drug in the non-randomised follow-up studies were selected to do better. This could explain the lack of ‘catch-up’ in the unselected group who initially started on placebo but then switched later. The extent of this bias is not known.

It is possible that patients with very mild AD are more likely to experience cholinergic side-effects (III). Furthermore, there is no evidence that patients with mild cognitive impairment which does not reach criteria for dementia benefit from ChEIs and there is evidence of an increased risk of harm, including an increased death rate.

In summary, the case that patients should take ChEIs early because they will otherwise not ‘catch up’ is not proven and there may be an increase in risk of side-effects if started very early. On the other hand, patients with mild AD derive the same overall clinical benefit from ChEIs as those with moderate AD, although the benefit in terms of performance on cognitive scales is smaller in mild than in those with moderate AD.

Conclusion: It is recommended that ChEIs are started at the point of diagnosis of mild AD (I).

Choice of drug

There are no significant differences between the ChEIs in size of beneficial effect (II). The few head-to-head comparative studies are all industry sponsored, small, inconsistent in results, and offer little basis to make a clinical choice (I). The choice depends on the experience of the clinician, tolerance of side effects, ease of use, and the clinical profile of the individual to be treated (such as weight, co-morbid diseases). Oral rivastigmine is shorter acting and more likely to cause GI side effects at high doses than other oral ChEIs (III) but the patch formulation is better tolerated (II).

Side effects

Approximately 50% of patients experience some form of side-effect with ChEIs (II). Side effects are slightly more common when ChEIs are given in early dementia or MCI (III) and may reflect milder cholinergic deficits (III). The occurrence of side effects should not preclude a subsequent cautious trial at a later stage of dementia (I).

As a class, the commonest side-effects are nausea, vomiting, diarrhoea, loss of appetite, headache and dizziness (I). Peptic ulceration and bradycardia are potentially the most serious acute side-effects but are uncommon (I). Lowered heart rate may cause dizziness, fatigue or light-headedness and gives rise to possible interactions with drugs that slow down heart rhythm such as digoxin and beta-blockers (I). Rhinitis, urinary frequency, fatigue and worsening of confusion are not infrequent (II).

The side effects of ChEIs and their frequency as reported in the Summary of Product Characteristics are listed below

Common side effects of Cholinesterase Inhibitors

Table adapted from Summary Product Characteristics for donepezil, galantamine, rivastigmine.

The most common reason for lack of tolerability is nausea. This may respond to an anti-emetic such as domperidone 10mg three times daily (II). Emphasis should be placed on the need to take the drug in the middle of a meal since this may improve tolerability (III). Some suggest that the drug is better taken at night because the ‘nausea occurs when the patient is asleep’.

Drug interactions

ChEIs should not normally be used concurrently with other cholinomimetic drugs or strongly anticholinergic drugs (I). A synergistic effect is theoretically possible with succinylcholine and other neuromuscular blockers though this is rarely a problem in practice (II).

Drugs affecting the hepatic P450 system may affect the concentrations of donepezil and galantamine

• Inhibitors of CYP2D may increase the concentrations (quinidine, paroxetine, fluoxetine and fluvoxamine)
• Inhibitors of CYP3A4 may increase the concentrations (ketoconazole, itraconazole, erythromycin)
• Enzyme inducers may decrease the concentrations (rifampicin, phenytoin, carbamazepine, alcohol)

Compliance and formulations

Where medication compliance is an issue, once-daily oral or patch formulations are helpful. For patients with swallowing difficulties, patch, liquid or orodispersible formulations are helpful. It is common practice for patients with dementia who are taking tablets or capsules to have their medication administered by care givers or to have them presented in individual dosage boxes.

Rarely, short-term covert administration of medication is justifiable to patients who lack insight (III). However, covert administration should only be given on a continuing basis if there is documented evidence that the patient has very clearly benefited from a short-term trial (e.g. 2-3 months), continues to lack insight, has had no side-effects, and the decision is formally reviewed regularly (I). Consideration should be given to a trial without medication to confirm the continuing benefit in cases where medication is administered covertly (III).

Dosing information

* PR: prolonged release once-a-day formulation. The immediate-release formulation has been phased out.

† Solution can be mixed with non-alcoholic beverage, but must be consumed immediately.

Size of effect

The patient should be informed of the modest and unpredictable size of benefit and the unknown time before the patient declines to their current level (I). The following may be useful ways of expressing the benefit.

The use of a ChEI is followed by modest benefits in a substantial minority (30-40%) of patients. This amounts to a 3-point difference on the 70-point Alzheimer’s Disease Assessment Scale over a 6-month period. Approximately 20-35% percent of patients show an improvement which is equivalent to one year’s decline. However, significant numbers of patients respond to placebo, so ChEIs cause the condition to be stabilized or improved only in every seventh patient, and the general impression to be improved in every twelfth patient. We do not know for certain whether or not ChEI therapy confers benefit in terms of reducing the average time before institutionalisation is needed – there is evidence to support both possibilities (II).

The overall duration of benefit is unknown. It is known to be at least 24 months for donepezil (II)(48).

Dose titration

The dose should be titrated upwards over 4-8 weeks (I).

This titration should initially proceed up to the maximum tolerated, or maximum licensed, dose (I). There is evidence that patients who were titrated to higher doses exhibited better outcomes than those who received lower doses (I). However, it is not known whether this is because patients with greater cholinergic deficits are preferential responders and are less likely to have adverse reactions at higher doses. The pursuit of maximum tolerated dose should therefore be tempered by careful attention to persistent mild side effects such as nausea (II). Conversely, if the patient derives benefit which is considered satisfactory from a submaximal dose, then this dose can be continued (I). Subsequent further deterioration may then prompt an increase in dose (II).

Assessment of response

During the titration phase it is common practice to assess patients monthly (III). Thereafter, regular assessment, every six to twelve months is recommended (II).

In jurisdictions where the MMSE is not a specified criterion for treatment, there is no consensus about whether it is necessary routinely to use the mininmental state examination, or any other instrument, as part of the assessment. This is because the criterion for stopping treatment is based on a global clinical judgement. Whilst some care-givers find such assessment a helpful ‘objective’ validation of their experience of improvement or decline, others do not think that it usefully adds to their experience.

Mild Cognitive Impairment

ChEIs are not recommended for use in MCI (I). There is no evidence that patients with mild cognitive impairment which does not reach criteria for dementia benefit from ChEIs. There is evidence of an increased risk of harm, including death. The judgement about when a patient with MCI has declined to the point of dementia is should be based on assessment of the functional impact of the disease (I).

Partial response at maximal dose

When patients have responded well to each dose increment and have not experienced side-effects, cautious increases above the maximum dose recommended by manufacturers can be considered (III).

Approach to lack of response

There is insufficient randomised evidence that ChEIs reduce progression of underlying disease to justify a recommendation for either continued medication, or for cessation of medication, in the face of continued absent response. Whilst there is some evidence that treatment response at 3 months does not predict whether the patient will still be classed as a responder at 6 months or a year, such evidence is drawn from single selected trials and may be due to regression to the mean. Patients and carers may not wish to continue taking the small risks of continuing medication. If the patient derives no apparent initial benefit from the drug, for example after three months, then it is reasonable either to continue or to stop the drug, or to switch to another ChEI (III). Although there is evidence that standard doses of ChEI inhibit only 20% of the brain cholinesterase, there is no clinical evidence to support the addition of a second ChEI (III).

Switching ChEIs

There is evidence that if one drug is not tolerated, a second one might be (II).

The evidence that patients benefit from switching to a second drug because the first has been ineffective is weak (and not recommended in some countries)

Drug holidays

Drug holidays to determine whether the patient is continuing to benefit should be discouraged as they can be associated with clinical deterioration that may not revert to baseline even on resumption of therapy (III). There is no good evidence as to whether it is possible to ‘rescue’ such deterioration by rapid resumption within 2 weeks in the event of clinically apparent decline (II).

ChEIs should be continued during acute illness and hospitalizations, unless contraindicated. If stopped, it should be resumed as quickly as possible

Severe dementia

ChEIs should be continued if tolerated until the physician and caregiver consider the risk-benefit to be unfavourable (I). Unfortunately, there is no evidence at present to guide when this should be. The lower limit of cognitive function defining ‘moderate’ AD is not defined in the license. Most licensing trials excluded patients with an MMSE lower than 10. Donepezil is of proven benefit in severe AD and has a license for this use in severe AD in US and Canada. However, none of the drugs has a European license for use in severe AD.

However, there is little merit in continuing ChEI in patients who advance to "profound" disease and who have lost all cognitive and functional abilities (III).

Physician’s obligations in jurisdictions where public funding is restricted

Where it is possible that the patient could realistically exercise the choice to obtain and pay for the drug themselves, the doctor has a clear ethical obligation to inform the patient of the potential benefit and risks of drugs for which public funding is not available, including its modest and unpredictable size and duration (I).

The doctor does not have an ethical obligation to personally facilitate the exercising of such choice (III).

Where the doctor is sure that the patient would not be able to exercise such choice, for example because of unavailability of either a prescriber, or of the drug, or of financial resources, the ethical obligation on the physician to inform the patient that potentially beneficial drugs exist is less clear-cut.

If the patient is receiving drugs through another source, their treating doctor retains a responsibility to be aware of, and where necessary advise the patient of, possible side-effects and interactions with other medication (I).

Possible Alzheimer's disease

Where the diagnosis of possible AD rests on the fact that there is a single, gradually progressive severe cognitive deficit (typically of memory) identified in the absence of other identifiable cause and this is sufficient to affect social or occupational function, then a trial of ChEI is recommended (II).

Vascular dementia and mixed Alzheimer's and cerebrovascualr disease

The substantial overlap in clinical presentation between AD and VD, and in the risk factors for the two conditions, means that the majority of patients with cognitive impairment probably have both cerebrovascular and Alzheimer’s pathology. There is however, a spectrum. Some patients have predominantly Alzheimer’s pathology, others have predominantly cerebrovascular disease.

The key feature which distinguishes between those meeting clinical criteria for vascular dementia, and those with a diagnosis of Possible AD with cerebrovascular disease is the time course of the cognitive decline. Those who have neither an abrupt step-wise deterioration nor a decline which follows shortly after a stroke do not fulfil criteria for Probable VD. Despite this, the clinical criteria for Probable VD used in trials include patients with widely differing pathologies: from those with clear-cut infarcts and localising signs, to those with no localising signs, a fluctuating course and pervientricular white matter change.

Donepezil is associated with a significantly increased risk of death in trials of patients with possible or probable VD. In trials of galantamine, cognitive improvement was confined to those with more diffuse vascular pathology but there was no improvement in ADL, a fact which was attributed to the heterogeneity of ADL performance amongst those with varying degrees of vascular pathology. There is no good evidence to suggest that those who develop dementia following single cortical infarcts do well on ChEIs.

The lack of consensus on where the diagnostic boundaries of these conditions lie militates against strong recommendations. Nevertheless, the risk of harm means that routine use of ChEIs in patients with vascular dementia is not recommended (III). In particular, ChEIs are less likely to be helpful in those with clearcut localising signs and cortical infarcts (III). Known coexisting cardiovascular disease should be the dominant feature determining clinician’s use of ChEIs in the remainder of ‘Mixed’ cases (III).

However, vascular risk factors should not, in themselves, preclude use of ChEIs (III).

Memantine

Memantine is licensed for the treatment of moderate and severe AD. It is not licensed for vascular dementia. Similarly it is not approved for use in mild and no claims are made for a disease modifying action. The upper limit of ‘moderate AD’ was defined in the licensing trials as a Minimental State Examination score of 20.

There is consistent evidence of a small beneficial effect in all domains in patients with AD and an MMSE of 20 or below. It is recommended that patients in this category receive a trial of memantine (I).

The drug is routinely titrated upwards in 5mg increments to a total of 10mg twice daily from the fourth week. Side-effects were less common on 20mg than 30mg daily. A long acting formulation is the subject of a current licensing application.

Size of effect

The patient should be informed of the small and unpredictable size of benefit and the unknown time before the patient declines to their current level (I). The following may be useful ways of expressing the benefit.

Memantine slightly reduces decline after 6-months. This amounts to 3 points on 100 point Severe Impairment Battery over a 6-month period. Approximately 20-35% percent of patients show an improvement which is equivalent to one year’s decline. However, significant numbers of patients respond to placebo, so ChEIs cause a benefit in every tenth patient. (II).

The overall duration of benefit is unknown. A one year placebo controlled trial (Lundbeck 10112) is scheduled to report in Summer 2009. This is also powered to assess whether memantine has an effect in delaying disease progression as assessed by structural MRI.

Stopping memantine

The small effect size of memantine means that it is usually difficult to determine whether the drug is having a beneficial effect. The aims of therapy, and the response to a lack of apparent effect, should therefore be agreed with caregivers before starting memantine.

There is evidence that patients with an MMSE below 10 continue to benefit. However, it is not known whether memantine delays loss of basic ADLs in very severe cases. Discussion with family members about the aims of continued therapy is required at that stage.

Memantine and agitation

The possibility that memantine prevents the occurrence of agitation was suggested on the basis of analysis of adverse events from the first three trials in moderate to severe AD. An analysis of patients with behavioural disturbance from these trials supported this possibility (49). However, potentially confirmatory data from the subsequent four trials have not been forthcoming. This important question will be directly answered by trial Lundbeck 10158 which is scheduled to report in first half of 2009.

Side effects

Memantine is a well tolerated drug. The most common side effects are dizziness and somnolence.

Other treatments for cognitive symptoms of dementia

Ginkgo biloba

There is good evidence from the recently reported 5 year GEM study of 3069 participants that Ginkgo biloba has no effect in preventing dementia (50). The evidence of benefit on cognitive function in established dementia or AD is inconsistent and contradictory (51).

Ginkgo biloba is not recommended for prevention (I) or treatment (II) of dementia.

The numerical, although not statistically significant, excess of incident dementia in patients treated with ginkgo compared to placebo illustrate why it is untenable to recommend a drug or nutraceutical in the absence of efficacy evidence simply because it could possibly help and initially appears harmless.

Other drugs

This, coupled with lack of evidence of efficacy in high quality RCTs, is why the following, which have all been variously asserted as having potential for treatment of dementia are not recommended as treatments for dementia (II):