Nature Reviews Neurology 6, 418-420 (August 2010) |doi:10.1038/nrneurol.2010.105
Drugs acting on the cholinergic system can improve or worsen cognitive abilities, and their effects are particularly pronounced in frail elderly individuals and patients with Alzheimer disease. Guidelines are urgently needed on the judicious use of cholinergic drugs.
Cholinesterase inhibitors remain pivotal to the treatment of Alzheimer disease (AD), but no specific guidelines are currently available regarding appropriate switching and discontinuation of these drugs. Gardette et al. sought to identify predictive factors of discontinuation and switching of cholinesterase inhibitors over a 2 year period in a multicenter cohort of community-dwelling patients with mild to moderate AD (Mini Mental State Examination score 10–26).1 Of the 686 patients enrolled, 611 were treated with cholinesterase inhibitors at baseline and scheduled for biannual follow-up. At 2 years, only 326 patients attended the fifth and final visit. Cholinesterase inhibitor switch and discontinuation incidence rates were 9.2 per 100 person-years (median time to event 10 months) and 3.6 per 100 person-years (median time to event 5 months), respectively. Ineffective cholinesterase inhibitor dose (adjusted hazard ratio [HRa] 6.91), rapid cognitive decline (HRa 4.10), hospitalization unrelated to AD (HRa 2.33) and anxiety score ≥4 on the Neuropsychiatric Inventory (HRa 2.08) were independently and significantly associated with switching to another cholinesterase inhibitor. Use of anticholinergic medication (HRa 4.26), hospitalization (AD-related: HRa 9.14, not AD-related: HRa 4.23), and weight loss (HRa 3.77) were independently and significantly associated with discontinuation of cholinesterase inhibitors.
Gardette et al. hypothesized that rapid cognitive decline was a marker for disease progression and often led to switching to another cholinesterase inhibitor in order to obtain a better response.1 Anxiety might be a predictive factor for switching because patients exhibiting anxiety related to their disease are surrounded by anxious caregivers who ask for a medication change on the patient's behalf. Alternatively, anxiety could be an adverse effect of the cholinesterase inhibitor itself or a symptom of the illness recognized by the clinician, leading them to change the patient's medications. The authors suggested that an ineffective dose of cholinesterase inhibitor could be explained by intolerance to medication, which would ultimately lead to switching.
Gardette et al. point out that weight loss is often seen with progression of AD and might, therefore, be a marker for end-stage dementia, at which stage cholinesterase inhibitors may be stopped owing to their uncertain benefits.1 The authors explain that a specialist might also choose to stop cholinesterase inhibitors when the patient is concomitantly receiving anticholinergic drugs because of awareness of the inappropriateness of the combination or perceived lack of effectiveness of the cholinesterase inhibitors. Why a specialist would choose to discontinue the cholinesterase inhibitors as opposed to the anticholinergic medications, however, is difficult to explain. Hospitalization seems to be a time where the efficacy and tolerance of cholinesterase inhibitors are reassessed, leading to switching (when the hospitalization is not AD related) or discontinuation (regardless of cause of hospitalization). Alternatively, changes in medication might reflect the internist's preference and knowledge of cholinesterase inhibitors. As suggested by Gardette et al., hospitalization for non-AD reasons can lead to stopping or changing cholinesterase inhibitors in light of a newly discovered contraindication or new drug–drug interaction.
Gardette et al.'s study has several limitations.1 Given that the patients were enrolled from AD expert centers, a selection bias might have been present. At the time of study enrollment, 531 of the patients had been on cholinesterase inhibitors for a median period of 6 months (the drugs were prescribed to the remaining 80 patients during the initial visit). The majority of the patients, therefore, had already demonstrated that they could tolerate the drugs, as most adverse effects with this type of medication are seen shortly after initiation. In addition, patients who have found the medication to be effective are more likely to continue with the treatment than are non-responders. These caveats might explain why Gardette et al.'s low discontinuation rate was incongruent with earlier persistence data obtained from pharmacy claims and randomized trial studies. Time to switch or discontinuation was calculated from the time of study inclusion and not from initiation of cholinesterase inhibitors, thereby limiting the usefulness of the resulting information. Given the high drop-out rate at 2 years, an attrition bias could also be present.
AD is conceptualized as a state of acetylcholine deficit. Cholinesterase inhibitors all inhibit the acetylcholinesterase enzyme, thereby increasing the amount of available acetylcholine. The differing pharmacodynamic and pharmacokinetic profiles of the cholinesterase inhibitors available on the market explain why these medications might have different efficacies and adverse effects in a given individual. Lack or loss of efficacy of, or intolerance to one cholinesterase inhibitor might prompt a switch to another drug in this class. The British Association for Psychopharmacology Dementia Consensus Group concluded that type 2b evidence exists to support switching to another cholinesterase inhibitor for reasons of inefficacy or intolerance.2
The question of when to discontinue cholinesterase inhibitors remains elusive. Most randomized controlled trials of cholinesterase inhibitors have lasted no longer than 6 months. Studies have, however, shown that patients can still benefit from cholinesterase inhibitors even after they have developed severe AD.3
One of the important issues raised by Gardette et al.'s study is the concomitant use of anticholinergic medications in patients receiving cholinesterase inhibitors. In this study, 6–9% of patients were receiving anticholinergic medications at one of the visits to the clinic. This figure is surprisingly high given that these patients were recruited at AD expert centers, where specialists are likely to be aware of the inappropriateness of the combination. In primary care clinics, the proportion of patients receiving both classes of medication is likely to be even higher. In a Canadian study by Herrmann et al.,4 37% of 28,961 patients treated with cholinesterase inhibitors were concomitantly receiving anticholinergic medications or benzodiazepines. In a Rhode Island Medicaid program study,5 60% of 1,183 patients taking cholinesterase inhibitors were also receiving medications known to impair cognition. These patients were less likely than the others to continue cholinesterase inhibitor therapy after 6 months. Clinicians should carefully weigh up the risks and benefits of prescribing anticholinergic medications in patients with AD. In Gardette et al.'s study, the anticholinergic drugs most often prescribed were hydroxyzine—an antihistamine prescribed for allergic reactions and sometimes for agitation or anxiety—and urinary antispasmodics.1 Cetirizine (a major metabolite of hydroxyzine) and loratadine are antihistamines that exhibit poor penetration of the blood–brain barrier and might, therefore, represent alternatives for the treatment of allergic reactions. Nontricyclic antidepressants such as selective serotonin reuptake inhibitors can be tried for the treatment of anxiety and agitation instead of hydroxyzine. To treat incontinence in patients with AD, behavioral modification or prompted voiding, rather than the use of antispasmodics, should be encouraged in the first instance. Optimizing the use of incontinence pads could be another alternative to antispasmodics. In the Gardette et al. study, 16.9% of patients were receiving benzodiazepines, but the authors do not specify whether use of these drugs was regular or sporadic. Benzodiazepines are associated with impaired cognition as well as falls and fractures in the elderly, and should be used sparingly.
In conclusion, Gardette et al.'s study sheds light on the factors that predict switching and discontinuation of cholinesterase inhibitors in mild to moderate AD. More importantly, the study illustrates the importance of developing clear guidelines for switching and discontinuing cholinesterase inhibitors and the need to familiarize clinicians with the judicious use of medications that can impair cognition.
References
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Gardette, V. et al. Predictive factors of discontinuation and switch of cholinesterase inhibitors in community-dwelling patients with Alzheimer's disease: a 2-year prospective, multicentre, cohort study. CNS Drugs 24, 431–442 (2010).
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Burns, A. et al. Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology. J. Psychopharmacol. 20, 732–755 (2006).
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Rodda, J. & Walker, Z. Ten years of cholinesterase inhibitors. Int. J. Geriatr. Psychiatry24, 437–442 (2009).
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Herrmann, N. et al. A population-based study of cholinesterase inhibitor use for dementia. J. Am. Geriatr. Soc. 55, 1517–1523 (2007).
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Kogut, S. J., El-Maouche, D. & Abughosh, S. M. Decreased persistence to cholinesterase inhibitor therapy with concomitant use of drugs that can impair cognition.Pharmacotherapy 25, 1729–1735 (2005).
