Donepezil, rivastigmine, galantamine and memantine for ...

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66 Clinical effectiveness (24 mg/day). When studies are pooled no statistically significant effects are demonstrated. ● Three RCTs assessed mean changes from baseline on the DAD scale, all reporting statistically significantly slower deterioration for those receiving galantamine 24–32 mg/day compared with placebo. Two RCTs found that participants receiving 16 and/or 24 mg/day galantamine experienced a statistically significantly smaller deterioration on the ADCS/ADL compared with placebo. ● Two published [commercial/academic confidential information removed] RCTs found that galantamine had some effect in improving or limiting further deterioration on the NPI scale compared with placebo. Differences in the mean change from baseline were statistically significant for doses of ≥16 mg/day in one of the three studies. ● Adverse events affect participants receiving galantamine more than those on placebo, with between 2 and 27% more participants suffering an adverse event. Nausea, vomiting, dizziness, diarrhoea and anorexia were the main adverse events. Withdrawals due to adverse events resulted in a loss of between 6 and 44% of galantamine participants, with differences following a dose–response relationship. ● The six published [commercial/academic confidential information removed] RCTs show benefit for participants receiving galantamine compared with placebo on the outcome measures of ADAS-cog, CIBIC-plus, NPI and DAD, with doses of 16–32 mg/day appearing to be the most effective. Lower doses appear to have limited effect and higher doses have some detrimental effects, particularly in terms of adverse events. Studies were of a short duration and it is difficult to judge the long-term consequences. In addition, it is difficult to assess what the changes on these outcomes mean for people with AD and carers, especially as there are no studies assessing QoL. Head-to-head drug comparisons Quantity and quality of research available Three RCTs met the inclusion criteria for the review. Two compared donepezil with rivastigmine68,69 and one compared donepezil with galantamine. 70 Details of the study characteristics are given in Table 33. Donepezil versus rivastigmine Two trials compared donepezil with rivastigmine. Doses of both treatments were different between the two studies. In Fuschillo and colleagues’ 68 study, those in the donepezil group were given 5 mg/day and those in the rivastigmine group had 1.5 mg/day for 1 week, increasing weekly in steps of 1.5 mg up to 6–9 mg/day. In Wilkinson and colleagues’ 69 study, those in the donepezil arm were given 5 mg/day for 28 days followed by 10 mg/day; those in the rivastigmine arm were initially given 1.5 mg twice daily for 14 days, then 3 mg twice daily for 14 days, then 4.5 mg twice daily for 14 days and finally, if tolerated, were given 6 mg twice daily. Fuschillo and colleagues’ 68 study was a single-centre study of just 27 participants. Wilkinson and colleagues’ 69 study was a multicentre study (19 centres) with 112 participants. Neither study reported whether sample size calculations was made. The duration of treatment was 30 and 12 weeks in the Fuschillo 68 and Wilkinson 69 studies respectively. Donepezil versus galantamine In the trial comparing donepezil with galantamine, those in the donepezil arm were given 5 mg/day for 28 days followed by 10 mg/day; those in the galantamine arm were initially given 4 mg twice daily for 28 days, then 8 mg twice daily for 28 days and then 12 mg twice daily. The RCT was a multicentre study with 120 participants. This study calculated sample sizes and was able to recruit to this number. The duration of treatment was 12 weeks. Quality assessment The quality of reporting and methodology of the included RCTs was generally poor by today’s standards (see Table 34). The method of randomisation was adequate only in the donepezil–galantamine trial 70 and concealment of allocation was inadequate in all trials. These factors increase the risk of selection bias, with the allocation sequence open to possible manipulation. All trials reported adequate eligibility criteria, and all report whether their comparison groups were similar at baseline or not. As all three trials were open-label RCTs owing to the nature of the comparisons, assessment of blinding of the care provider and patient is classed as not applicable. However, blinding of outcome assessors would be viable, but this was not judged to be adequate in any of the studies. In two studies the outcome assessors were blinded for one outcome; however, this was not the case for the other outcomes reported. These are therefore rated as partial on this criterion. None of the trials included an appropriate ITT analysis. 50 Two of
TABLE 33 Characteristics of included studies for head-to-head comparisons © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 1 Study Methods Participants Outcomes Donepezil versus rivastigmine Fuschillo et al., 2001 68 Wilkinson et al., 2002 69 Donepezil versus galantamine Jones et al., 2004 70 Design: RCT Interventions: 1. Donepezil 5 mg/day 2. Rivastigmine 1.5 mg/day for 1 week, increasing weekly by steps of 1.5 mg/day to 6–9 mg/day Number of centres: 1 Duration of treatment: 30 weeks Sponsor: not reported Design: RCT, multicentre Interventions: 1. Donepezil 5 mg/day for 28 days then 10 mg/day 2. Rivastigmine 1.5 mg b.d., increasing to 3 mg b.d. (day 14), 4.5 mg b.d. (day 28) and finally 6 mg b.d. (day 42) if tolerated Number of centres: 19 Duration of treatment: 12 weeks Sponsor: Eisai and Pfizer Design: RCT, multicentre Interventions: 1. Donepezil 5 mg/day for 4 weeks, then 10 mg/day 2. Galantamine 4 mg b.d. for 4 weeks, 8 mg b.d. for a further 4 weeks, then 12 mg b.d. Number of centres: 14 Duration of treatment: 12 weeks Sponsor: Eisai and Pfizer Pharmaceuticals TABLE 34 Quality assessment table for head-to-head comparisons Study Randomisation Concealment of allocation Baseline characteristics Inclusion criteria: AD (DSM-IV and NINCDS-ADRDA); MMSE 10–21 Numbers: 27 randomised: 1. 16 to donepezil 5 mg/day 2. 11 to rivastigmine 1.5–9 mg/day Mean age ± SD (range): 1. 68.1 ± 5.6 (54–77) 2. 66.2 ± 9.2 (53–77) Inclusion criteria: ≥ 50 years old; mild to moderate, possible or probable AD (DSM-IV and NINCDS-ADRDA); MMSE 10–26 Numbers: 112 participants randomised: 1. 57 a to donepezil 5 mg/day 2. 55 to rivastigmine 3–12 mg/day Mean age ± SD (range): 1. 74.0 ± 7.6 (51–87) 2. 74.9 ± 7.3 (52–90) a 1 patient in the donepezil group did not receive any study medication. Inclusion criteria: ≥ 50 years of age; probable or possible, mild or moderate AD (DSM-IV and NINCDS-ADRDA); MMSE 10–24 Numbers: 120 randomised: 1. 64 to donepezil 2. 56 to galantamine Mean age ± SD (range): 1. 73.8 ± 7.4 (51–88) 2. 75.1 ± 7.7 (53–89) Primary outcomes: ● MMSE ● ADAS-cog ● Physical Self Maintenance Scale (PSMS) of the ADL test Secondary outcomes: ● Adverse events Primary outcomes: ● ADAS-cog (11-item version) ● MMSE Secondary outcomes: ● Adverse events Primary outcomes: ● Physician’s and Caregiver’s Satisfaction Questionnaires (P&CSQ) Secondary outcomes: ● ADAS-cog (11-item and 13-item versions) ● MMSE ● DAD ● Adverse events Donepezil versus rivastigmine Fuschillo et al. 68 Un Un Rep Ad In NA NA Ad In Un Wilkinson et al. 69 Donepezil versus galantamine Un Un Rep Ad Par NA NA Ad In Ad Jones et al. 70 Ad Un Rep Ad Par NA NA In In Ad Ad, adequate; In, inadequate; Par, partial; Rep, reported; Un, unknown; NA, not applicable. Eligibility Blinding of assessors Care provider blinding Patient blinding Reporting outcomes ITT analysis Withdrawals explained 67
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Health Technology Assessment 2006;
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The clinical and cost-effectiveness
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Objectives: To provide an update re
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List of abbreviations .............
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AChEI acetylcholinesterase inhibito
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Epidemiology and background Alzheim
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Galantamine Five published economic
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Description of underlying health pr
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TABLE 1 Estimated prevalence of AD
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as one component of their care. A n
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Data synthesis Data were synthesise
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14 Clinical effectiveness TABLE 3 C
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1. Clegg A, Bryant J, Nicholson T,
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placebo-controlled study of donepez
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94. Brooks E, Deal L. The effect of
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of memantine in patients with moder
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