Authors' objectives: Background: Currently, no disease-modifying treatment is available for Alzheimer disease (AD) or Parkinson’s disease dementia (PD). Professional societies in Switzerland generally recommend symptomatic treatment using non-pharmacological therapies, and to add antidementia drugs when needed. However, scientific literature is inconclusive about the clinical benefit of antidementia drugs. A health technology assessment (HTA) was requested to compare the available evidence on Acetylcholinesterase (AChE) inhibitors and memantine for the symptomatic treatment of AD and PD. Objective: This HTA examines the efficacy, effectiveness, safety and cost-effectiveness of antidementia drugs compared to treatment without antidementia drugs or placebo in AD and PD and presents the health economic impact of a potential removal of these drugs from the list of pharmaceutical specialties in Switzerland. Furthermore, ethical, legal, social and organizational aspects are considered. Research questions: Is it efficacious, effective, safe and cost-effective 1) to treat mild to moderately severe AD patients with donepezil, galantamine or rivastigmine compared to not treating them with antidementia drugs? 2) to treat moderate to severe AD patients with memantine compared to not treating them with memantine? 3) to treat mild to moderately severe PD patients with rivastigmine compared to not treating them with rivastigmine? What is the budget impact of donepezil, rivastigmine, galantamine and memantine? Are there ethical, legal, social, or organizational issues related to antidementia drugs?

Authors' results and conclusions: Results: Regarding treatment with donepezil, galantamine or rivastigmine in mild to moderately severe AD patients, 24 RCTs were included in the analysis. 15 trials investigated donepezil, 6 trials rivastigmine and 3 trials galantamine. The certainty of evidence for the critical outcomes was judged as low to high, with evidence pointing at better results on cognition, function and global outcomes for AChE inhibitors compared to placebo in patients with mild to moderate dementia due to AD. Serious adverse events were higher for AChE inhibitors at one year of follow-up. Regarding treatment with memantine in moderate to severe AD patients, only two RCTs were identified. We found better results for memantine compared to placebo in patients with moderate to severe dementia due to AD on the domains of function and global outcomes with moderate certainty. With low certainty, there were no statistically significant differences with respect to mortality and serious adverse events. Regarding treatment with rivastigmine in mild to moderately severe PD patients, only one RCT was identified. This trial was rated with a high risk of bias and showed statistically significant better results on cognition, function, neuropsychiatric symptoms and global outcomes for rivastigmine compared to placebo in patients with mild to moderate dementia due to PD. Regarding safety, no statistically significant differences were identified. Based on a systematic review of health economic evaluations we retrieved 30 studies, 17 of which were considered transferable and were adapted for Switzerland. Seven studies investigated donepezil, galantamine or rivastigmine in mild to moderately severe AD patients and ten studies memantine in moderate to severe AD patients. Only one study was identified regarding rivastigmine in mild to moderately severe PD patients but was not considered transferable. Of the seven studies investigating donepezil, galantamine or rivastigmine in mild to moderately severe AD patients, four were regarding donepezil, three galantamine and no study was considered transferable regarding rivastigmine. Although these studies were considered transferable there is uncertainty related to their input parameters and assumptions. Regarding donepezil, galantamine or rivastigmine in mild to moderately severe AD patients, the results suggest that donepezil is not cost-effective over a time-horizon of up to 1.5 years. Over a time-horizon of 10 years, donepezil becomes dominant. Similarly, treatment with galantamine seems to be cost-effective over a time-horizon of 5 years. Regarding memantine in moderate to severe AD patients, four out of the seven adapted studies indicate memantine to be dominant. The other three studies indicate that memantine is cost-effective below a hypothetical threshold of CHF 100,000 per QALY. Regarding budget impact, a total removal of the AChE inhibitors or memantine would lead to additional costs ranging from CHF 1.01 million for galantamine to CHF 12.42 million for rivastigmine for the healthcare payers, attributable mostly to higher rates of institutionalization. In the extreme assumption that there is no treatment effect on institutionalization, stopping AD treatment with one of the AChE inhibitors or memantine would lead to savings that vary from CHF 0.80 million for galantamine to CHF 7.87 million for rivastigmine. Several ethical, legal, social, and organizational issues were identified concerning the use of antidementia drugs. A decision that would affect the use of these medications should respect patient autonomy and consider the consequences for the proxies. Another crucial ethical issue is the focus on cognitive and global outcomes in the trials that might leave out many much more relevant signs and symptoms, such as alterations of mood, anxiety, psychotic symptoms, and insomnia. From a legal perspective, a decision by the competent authorities must guarantee the protection of people with disabilities and elderly persons and consider the capacity of judgment. On the social domain, a high level of burden was noted in caregivers of dementia patients, and problems with access to antidementia drugs for some patients. A variety of organizational issues were discussed in the literature, from national dementia strategies to variations in antidementia treatment between different regions. Conclusion: Our results are consistent with previous findings from Cochrane reviews and other systematic reviews including meta-analysis. Despite statistically significant differences for many outcomes investigated, we come to the conclusion that the clinical relevance of the differences between the treatment with and without antidementia drugs is questionable based on published cut-off values for Minimal Clinically Important Difference (MCID). There is also no strong evidence in support of a difference on the safety outcomes between the two groups. All antidementia drugs can be cost-effective except for rivastigmine when used for the treatment of PD due to lack of published transferrable health economic studies. The budget impact caused by total removal of the AChE inhibitors or memantine could range between additional costs of up to CHF 12.42 million to savings of up to CHF 7.87 million in 2021. This remarkable range is related to the uncertainty of evidence regarding the delay of need of being transferred to institutionalized care.

Authors' methods: Methods: We conducted systematic literature reviews of evidence on the efficacy, effectiveness and safety and of health economic evaluations regarding the treatment with antidementia drugs compared to treatment without antidementia drugs or placebo in AD and PD. For the clinical evidence meta-analysis was performed for outcomes with sufficient available evidence. The certainty of evidence for relevant outcomes was assessed by applying the GRADE approach. The cost-effectiveness and cost-utility were assessed by transferring the results from international studies to Switzerland, while a budget impact model was built for the Swiss setting. Furthermore, a targeted search for evidence on the ethical, legal, social and organizational aspects of antidementia drugs was conducted and findings were qualitatively summarized and discussed.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/medikamentebeialzheimerdemenz.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0048alzh-hta-protocol.pdf.download.pdf/h0048alzh-hta-protocol.pdf

Year Published: 2022

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0048alzh-hta-report.pdf.download.pdf/h0048alzh-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health