Ginkgo biloba Extract (EGb761), Cholinesterase Inhibitors, and Memantine for the Treatment of Mild-to-Moderate Alzheimer's Disease: A Network Meta-Analysis.

BACKGROUND: Cholinesterase inhibitors (ChEIs) and memantine have been reported to provide modest benefits for cognition and aspects of functioning in Alzheimer's disease (AD). Ginkgo biloba extract (EGb761), a phytomedicine, is widely used and expected to be well-tolerated. A few trials have compared EGb761 with ChEIs, and the results were inconclusive. OBJECTIVE: A network meta-analysis was conducted to evaluate the therapeutic benefits and tolerability of EGb761, three ChEIs (donepezil, galantamine, and rivastigmine), and memantine in mild-to-moderate AD patients. METHODS: Electronic databases were searched through 30 June 2017. We included randomized double-blinded trials with a minimum treatment duration of 22 weeks for EGb761 240 mg/day and 12 weeks for ChEIs or memantine. The study patients included AD or probable AD patients without other types of dementia or neurological disorders. Cognition, function, and behavior symptoms were compared between treatments using the standardized mean difference (SMD). Clinical global impression, treatment discontinuation, and adverse events were compared between treatments using the relative risk (RR). Statistical pooling of the individual trial results was conducted using a frequentist approach. The probability of being the best for a treatment was estimated using surface under the cumulative ranking. RESULTS: EGb761 and memantine showed no therapeutic benefits in all study outcomes. For cognition, all ChEIs were significantly better than placebo (SMD from - 0.52 to - 0.26), and galantamine was better than rivastigmine in the oral and patch forms, EGb761, and memantine (SMD [95% confidence interval (CI)]: - 0.22 [- 0.40 to - 0.05]; - 0.26 [- 0.45 to - 0.07]; - 0.34 [- 0.56 to - 0.12]; and - 0.42 [- 0.71 to - 0.13], respectively). Compared to placebo, galantamine, the rivastigmine patch, and oral rivastigmine provided modest functional benefits (SMD, from 0.21 to 0.24), and galantamine provided behavioral benefits (SMD [95% CI]: - 0.15 [- 0.26 to - 0.04]). All ChEIs provided a better improvement in clinical global impression than placebo (RR from 1.20 to 1.69). The global impression ratings were more improved with donepezil than with galantamine (RR [95% CI]: 1.40 [1.09-1.80]) or with EGb761 (RR [95% CI]: 1.40 [1.06-1.85]), with a 96% probability of donepezil being more effective than the other study agents. Rivastigmine in oral and patch forms, galantamine, and donepezil had a higher risk of being discontinued than placebo (RR [95% CI]: 2.14 [1.49-3.06]; 2.04 [1.30-3.20]; 1.79 [1.28-2.49]; 1.49 [1.03-2.17], respectively). Discontinuation of EGb761 was not statistically lower than that of the ChEIs, in which donepezil had the lowest probability (38%) of being discontinued. CONCLUSION: EGb761 and memantine showed no treatment benefits compared to placebo and ChEIs. Galantamine provided the highest beneficial effect on cognition and behavioral symptoms. Donepezil provided a better clinical global impression and tolerability than the other ChEIs and EGb761, with a similar benefit for cognition as galantamine.

Cost-Effectiveness Analysis of Direct-Acting Oral Anticoagulants for Stroke Prevention in Thai Patients with Non-Valvular Atrial Fibrillation and a High Risk of Bleeding.

OBJECTIVE: The objective of this study was to assess the cost effectiveness of direct-acting oral anticoagulants for stroke prevention in Thai patients with non-valvular atrial fibrillation and a HAS-BLED score of 3. METHODS: Total costs (US$) in 2017 and quality-adjusted life-years were estimated over 20 years using a Markov model. A base-case analysis was conducted under a societal perspective, which included direct healthcare, non-healthcare and indirect costs in Thailand. Clinical events for warfarin and utilities were obtained from Thai patients whenever possible. The efficacy of direct-acting oral anticoagulants was derived from trial-based East Asian subgroups and adjusted for time in the target international normalized ratio range of warfarin. RESULTS: In the base case, use of apixaban instead of warfarin incurred an additional cost of US$20,763 per quality-adjusted life-year gained. Substituting apixaban with rivaroxaban and rivaroxaban with high-dose edoxaban would incur an additional cost per quality-adjusted life-year by US$507 and US$434, respectively. Compared with warfarin, high-dose edoxaban had the lowest incremental cost-effectiveness ratio of US$9704/quality-adjusted life-year, followed by high-dose dabigatran (incremental cost-effectiveness ratio US$11,155/quality-adjusted life-year). The incremental cost-effectiveness ratios based on a payer perspective were similar. The incremental cost-effectiveness ratio was below Thailand's cost-effectiveness threshold when high-dose dabigatran and edoxaban prices were reduced by 50%. Changes in key parameters had a minimal impact on incremental cost-effectiveness ratios. CONCLUSIONS: For both societal and payer perspectives, high-dose edoxaban with a price below the country cost-effectiveness threshold should be the first anticoagulant option for Thai patients with non-valvular atrial fibrillation and a high risk of bleeding.