Donepezil, rivastigmine, galantamine and memantine for ...

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76 Clinical effectiveness TABLE 46 Adverse events for memantine Reisberg et al. 72 Adverse events: No. (%) Adverse event Memantine 20 mg/day (n = 126) Placebo (n = 126) p-Value vs placebo Any adverse event 106 (84) 109 (87) Not reported Agitation 23 (18) 40 (32) Not reported Urinary incontinence 14 (11) 14 (11) Not reported Urinary tract infection 7 (6) 17 (13) Not reported Insomnia 13 (10) 10 (8) Not reported Diarrhoea 12 (10) 10 (8) Not reported Tariot et al. 71 Adverse events: No. (%) Adverse event Memantine 20 mg/day (n = 202) Placebo (n = 201) p-Value vs placebo Adverse events reported in at least 5% of participants in either group 78% 72% Agitation 19 (9.4) 24 (11.9) Not reported Confusion 16 (7.9) 4 (2.0) p = 0.1 Fall 15 (7.4) 14 (7.0) Not reported Influenza-like symptoms 15 (7.4) 13 (6.5) Not reported Dizziness 14 (6.9) 16 (8.0) Not reported Headache 13 (6.4) 5 (2.5) p = 0.9 Urinary tract infection 12 (5.9) 10 (5.0) Not reported Urinary incontinence 11 (5.4) 6 (3.0) Not reported Accidental injury 10 (5.0) 16 (8.0) Not reported Upper respiratory tract infection 10 (5.0) 13 (6.5) Not reported Peripheral edema 10 (5.0) 8 (4.0) Not reported Diarrhoea 9 (4.5) 17 (8.5) Not reported Faecal incontinence 4 (2.0) 10 (5.0) Not reported TABLE 47 Withdrawals due to adverse events for memantine Reisberg et al. 72 Withdrawals due to adverse events: No. (%) 13 (10) 22 (17) Tariot et al. 71 Withdrawals due to adverse events: No (%) 15 (7.4) 25 (12.4) 10–14) and those with severe AD (MMSE score >10). A benefit of memantine compared with placebo was suggested for all outcome measures in both groups. The required caregiver time, as assessed by the Resource Utilization in Dementia score, was analysed. The result was statistically significant, indicating that caregivers spent less time with participants receiving memantine (difference between treatment groups, 45.8 hours per month; 95% CI: 10.37 to 81.27; p = 0.01). Adverse events Adverse events were reported in both studies. These are shown in Table 46. The number of participants withdrawing owing to adverse events is shown in Table 47. The majority of participants in the Reisberg and colleagues study 72 experienced adverse events (84% with memantine and 87% with placebo). Most adverse 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. Serious adverse events were reported in 16 (13%) of participants receiving memantine and 23 (18%) of participants receiving placebo. Most of the serious adverse events were considered to be unrelated to study medication. More participants receiving placebo than participants receiving memantine discontinued the study prematurely owing to adverse events. As can be seen from the Table 46, adverse events occurred in 78% of the memantine and 72% of the placebo groups in the Tariot and colleagues
study. 71 Most adverse events were rated as mild or moderate in severity and were judged not to be related to the study drug for participants in both treatment groups. The only adverse events that occurred in at least 5% of the memantine group and with an incidence of at least twice that of the placebo group were confusion and headache. By similar criteria, lower incidences of diarrhoea and faecal incontinence were observed in the memantine group compared with the placebo group. Other gastrointestinal effects of interest for participants receiving cholinesterase inhibitors included nausea (memantine group 0.5%; placebo group 3.5%) and constipation (memantine group 3.0%; placebo group 1.5%). Four (25%) of 16 participants experiencing confusion discontinued because of this adverse event compared with three (75%) of four participants receiving placebo who experienced this adverse event. In most of the participants receiving memantine, confusion was rated as mild, occurred at a median of 32 days and remitted within 2 weeks. In participants receiving placebo, confusion was more likely to be rated as severe, occurred at a median of 55 days and did not remit. No participants discontinued because of headache, which usually lasted 1 day. Withdrawals due to adverse events Both studies reported withdrawals related to adverse events and these are shown in Table 47. As can be seen from the results, there was not a very large variation in the number of people who withdrew between the two studies. Withdrawals due to adverse events ranged from 7.4 to 10% in the memantine group and from 12.4 to 17% in the placebo group. p-Values were not reported for either study. Withdrawals unrelated to adverse events were shown to be similar between groups in one included study, 72 and higher in the placebo group in the other study. 71 No statistical comparisons were made in either trial. Deaths were reported to be slightly higher in the placebo group in one study, 72 but again this was not tested for statistical significance. Data relating to withdrawals can be found in Appendix 11. Summary ● Two multicentre placebo controlled RCTs assessing doses of 20 mg/day of memantine over durations of 24–28 weeks met the inclusion criteria for the systematic review. Participants included were those with moderately severe to severe AD. The methodological quality and the quality of reporting in the studies were generally of a good standard. © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 1 ● Both RCTs investigating the use of memantine versus placebo showed some statistically significant improvements in outcomes for memantine compared with placebo. Both studies demonstrated that memantine appears to show a statistically significant benefit to participants on the ADCS/ADL when compared with placebo, with a reduction in the level of deterioration. Likewise, both studies used the CIBIC-plus as a measure of global outcome and, in both cases, memantine appeared to be effective. ● Both studies used the SIB as a measure of cognitive outcome. Statistically significant differences in favour of the use of memantine over placebo were apparent in the two studies, although a greater effect was shown in the study by Tariot and colleagues, 71 where an increase (0.9) in CIBIC-plus score occurred, rather than the study by Reisberg and colleagues, 72 where a deterioration in score occurred (–4.0). ● The two studies are not able to be combined in a meta-analysis owing to heterogeneity between the two patient groups, that is, participants already receiving donepezil versus participants not already receiving a cholinesterase inhibitor. The reporting of similar outcome measures in the two studies, such as the ADCS/ADL and the CIBIC-plus, tend to suggest, however, that a more favourable effect is apparent in the study by Tariot and colleagues. 71 It could be suggested, therefore, that memantine is more effective in participants who are already receiving donepezil and continue to do so. However, there are no other RCTs of this kind to compare with and therefore this statement cannot be made with any degree of conviction. It must also be pointed out that the study sample was larger (n = 404) than that in the study by Reisberg and colleagues 72 (n = 252). ● The frequency of adverse events was similar for both the memantine and placebo groups. In the Reisberg and colleagues 72 study, the incidence rates for frequently reported adverse events in the memantine group were no more than 2% higher than in the placebo group. Likewise, in the study by Tariot and colleagues, 71 the percentage of participants experiencing adverse events in the memantine and placebo groups was 78 and 72%, respectively. Withdrawals due to adverse events resulted in a loss of between 7.4 and 10% of memantine participants. ● The two RCTs show benefit for participants receiving memantine compared with placebo on the outcome measures of ADCS/ADL, CIBICplus and SIB, appearing to be most effective in participants already receiving a steady dose of 77
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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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The a priori methods used for syste
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Data synthesis Data were synthesise
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14 Clinical effectiveness TABLE 3 C
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16 Clinical effectiveness TABLE 3 C
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18 Clinical effectiveness particula
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20 Clinical effectiveness Compariso
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22 Clinical effectiveness TABLE 6 M
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24 Clinical effectiveness donepezil
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Page 94 and 95: 80 Evidence from systematic reviews
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126 Economic analysis TABLE 73 Prof
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128 Economic analysis Probability o
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130 Economic analysis Results are s
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132 Economic analysis 4. The model
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134 Economic analysis perspective e
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136 Economic analysis indicating th
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Ongoing research, with relevance to
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The increasing numbers of the very
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146 Discussion and conclusions dose
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148 Discussion and conclusions effo
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150 Discussion and conclusions Stre
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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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This version of HTA monograph volum
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376 Health Technology Assessment Pr
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378 Health Technology Assessment Pr
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