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Cholinesterase inhibitors such as galantamine and donepezil are among the few medications available that may slow the signs of dementia. However, their effects are modest, and the side effect profile may preclude their use in many patients. If additional benefit from these medications is found, it may encourage providers to prescribe these inexpensive and widely available agents. To explore other potential benefits of cholinesterase inhibitors, Dr. Truong and colleagues meta-analyzed the available clinical trial and longitudinal high-quality observational cohort data reporting mortality rates associated with cholinesterase inhibitor use vs placebo among patients with dementia. Across 24 included studies (n = 12 randomized clinical trials), there was a strong and significant reduction in the risk of death with cholinesterase inhibitor use among all-comers with dementia (adjusted RR 0.77, 95% CI 0.70–0.84). The estimated number needed to treat to avoid 1 death was 29. Similar effect estimates were confirmed across subgroup and in sensitivity analyses. Dr. Watt et al. commented on the technical aspects of the systematic review and meta-analysis, suggesting that the authors may have excluded other eligible trials and imprecisely assessed study bias. The authors note that many trials were excluded because of the short duration of the follow-up, which could have failed to capture any mortality difference (and would only be detectable after a considerable follow-up period). Additional clarifications were made regarding the analytic approach (protocol deviations) and the justification of post hoc comparisons, which have important clinical implications. Such secondary findings may shed light on treatment opportunities for specific populations of patients with dementia. This exchange underscores the value placed on a prespecified study methodology while also permitting an appropriate level of exploratory analyses that may be clinically relevant.
Cholinesterase inhibitors such as galantamine and donepezil are among the few medications available that may slow the signs of dementia. However, their effects are modest, and the side effect profile may preclude their use in many patients. If additional benefit from these medications is found, it may encourage providers to prescribe these inexpensive and widely available agents. To explore other potential benefits of cholinesterase inhibitors, Dr. Truong and colleagues meta-analyzed the available clinical trial and longitudinal high-quality observational cohort data reporting mortality rates associated with cholinesterase inhibitor use vs placebo among patients with dementia. Across 24 included studies (n = 12 randomized clinical trials), there was a strong and significant reduction in the risk of death with cholinesterase inhibitor use among all-comers with dementia (adjusted RR 0.77, 95% CI 0.70–0.84). The estimated number needed to treat to avoid 1 death was 29. Similar effect estimates were confirmed across subgroup and in sensitivity analyses. Dr. Watt et al. commented on the technical aspects of the systematic review and meta-analysis, suggesting that the authors may have excluded other eligible trials and imprecisely assessed study bias. The authors note that many trials were excluded because of the short duration of the follow-up, which could have failed to capture any mortality difference (and would only be detectable after a considerable follow-up period). Additional clarifications were made regarding the analytic approach (protocol deviations) and the justification of post hoc comparisons, which have important clinical implications. Such secondary findings may shed light on treatment opportunities for specific populations of patients with dementia. This exchange underscores the value placed on a prespecified study methodology while also permitting an appropriate level of exploratory analyses that may be clinically relevant.
Footnotes
Author disclosures are available upon request (journal{at}neurology.org).
- © 2023 American Academy of Neurology
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