Evidence - Based Evaluation And Clinical Study Of Drug Treatment For Vascular Dementia

Aim:To preliminarily observe the effectiveness and efficacy characteristics of method for calming liver and suppressing yang or method for promoting blood circulation to remove blood stasis in patients with mild to moderate vascular dementia(VaD), on the basis of evidence-based evaluation of drug efficacy and safety of VaD treatment.Methods:(1) Published literatures in CNKI periodical full text database, Wanfang Data knowledge service platform, VIP Chinese science and technology periodical database, PubMed and EMBASE were retrieved through computer. Retrieval date ended on July 4, 2015. All literatures were screened according to the inclusion and exclusion criteria, and study information was extracted. The Revman 5.3.5 software provided by the Cochrane collaboration network was used to evaluate the heterogeneity and to combine the results of the included studies.(2) All subjects were recruited from outpatient of the third encephalopathy department in Dongzhimen Hospital and community residents during October 2013 to June 2015. A total of 45 mild to moderate VaD patients were enrolled. A randomized, double blind, double placebo, parallel controlled design was carried out. All participants were randomly allocated to placebo (n=5), donepezil (n=20), or Chinese medicine for calming liver and suppressing yang (CM, n=20), and all entered a two-week placebo run-in period followed by a 24-week treatment period. The experiment medication and corresponding placebo were identical in appearance and taste.(3) All subjects were recruited from outpatient of the third encephalopathy department in Dongzhimen Hospital during November 2013 to June 2015 and from community residents. A total of 48 mild to moderate VaD patients were enrolled. A randomized, double blind, parallel controlled design was carried out. All participants were randomly allocated to placebo (n=24) or Chinese medicine for promoting blood circulation to remove blood stasis (n=24), and a two-week placebo run-in period followed by a 24-week treatment period were conducted to all patients. The experiment medication and placebo were identical in appearance and taste.Results:(1) Cholinesterase inhibitors (ChEIs) were superior to placebo in improving ADAS-cog (MD=-1.18, P<0.00001), VADAS-cog (MD=-1.01, P=0.002), MMSE (MD=0.52, P<0.00001) and CIBIC-plus (RR=1.29, P=0.0001) of mild and moderate VaD patients,but no statistical difference (P=0.26) inCDR-SB change were found between two groups; donepezil 10mg per day was slightly superior to 5mg/d in improving ADAS-cog and CDR-SB, but statistical difference (ADAS-cog:p=0.20;CDR-SB:p=0.08) were not found; Donepezil 5mg per day was significantly better than 10mg per day in CIBIC-plus improvement rate (RR=1.28, P=0.007), but there was no significant difference between donepezil 5mg per day and placebo (P=0.43). Memantine was better than placebo in improving ADAS-cog (MD=-2.18, P< 0.0001), but not statistically different with placebo in the change of NOSGER and GBS (NOSGER:P=0.36; GBS:P=0.12). On the improvement of CGI-item2, nicergoline was significantly better than placebo (MD=-0.74, P=0.001). On the improvement of ADAS-cog,cerebrolysin was significantly better than placebo (MD=-4,21, P=0.02). There was no significant difference between nimodipine and placebo in improving ZVT-G (P=0.14). NPI improvement was significantly better in EGb761 than placebo (MD=-6.63, P=0.04), but there was no statistical difference on SKT between EGb761 and placebo (P=0.10). Traditional Chinese medicine for tonifying kidney and promoting blood circulating was significantly better than placebo in improving BBS scores of patients with mild to moderate VaD (MD=-1.53, P<0.00001), but there was no statistical difference in MMSE score between CM and placebo (p=0.20). The overall adverse events of ChEIs group was higher than placebo group (RR=1.24, P= 0.03), adverse events occurred in donepezil 10mg per day group were significantly higher than those in the placebo group (RR=1.08, P= 0.002). The incidences of adverse eventsin memantine, nicergoline, cerebrolysin, nimodipine and EGb761 were not significantly different from placebo.(2) Both ITT-LOCF and PP analysis showed no difference on CIBIC-plus score and CIBIC-plus improvement rate between placebo group, donepezil group and CM group at week 24 (P1TT=0.333, PPp=0.305), it also showed no difference on CIBIC-plus scoreof different time points within each group (Pdonepezil=0.147 PCM=0.871). In ITT-LOCF analysis, the syndrome score of hyperactivity of liver yang was significantly improved from baseline in CM group at week 24 (P= 0.009), and was significantly better in CM group than in donepezil group at week 24 (p=0.049).In PP analysis, thehyperactivity of liver yang syndrome score of CM group at week 24was significantly improved than CM group at baseline (P= 0.004) and week 4 (P= 0.022), and was also significantly better than donepezil group (P= 0.008) and placebo group (P= 0.043) at week 24. In ITT-LOCF analysis,there were no significant differenceon MMSE, NPI and ADL improvement between three groups, and nosignificant differencebetween different time points within each group. Donepezil group showed superior improvement in MMSE language domain score thanCM group (P=0.017). Throughout the entire trial, there were a total of 34 cases of adverse events (AEs) and 13 cases in CM group. All AEs in the CM group were considered to have no relationship with the medication, and there were no significant difference in AEs rate between CM group, donepezil group and placebo group.(3) In ITT analysis, there was no significant difference on CIBIC-plus improvement rate between Chinese medicine for promoting blood circulation to remove blood stasis group and placebo group (p=0.238). At week24, the MMSE score change of Chinese medicine for promoting blood circulation to remove blood stasis group was significantly better than placebo(p=0.013) and Chinese medicine group at baseline(p=0.043).The ADL score change of Chinese medicine for promoting blood circulation to remove blood stasis group was significantly better than placebo at both week 12 and week 24(Pweeki2=0.000, Pweek24-0.001). Within group comparison showed that the blood stasis syndrome score was significantly improved from baseline (Pweek12=0.024, Pweek24=0.000) in CM group at both week 12 and week 24,meanwhile no significant improvement was found in blood stasis syndrome score in placebo group; Between group comparison showed that the Chinese medicine syndrome improvement was significantly better than placebo at week 24(p=0.001). To analyze the Chinese medicine syndrome elements, the tongue improvement in CM group was significantly better than placebo group(p=0.000), but no statistical difference was found between two groups on other 5 syndrome elements. In the whole process of the trial, there were 12 cases of AEs in total,8 cases (34.8%) in CM group and 4 cases (16.7%) in the placebo group. All cases were considered to have no relationship with medication, and no statistical difference were found in incidence of AEs between the two groups (p=0.193).Conclusion:(1) ChEIs and memantine and can improve cognitive function in VaD patients, but no efficient evidence confirmed their efficacy in improving overall impression and behavioral andpsychological symptoms.Cerebrolysin, nicergoline, EGb761 and Chinese medicine for tonifying kidney or promoting blood circulating may improvecognitive function, overall impression, psychiatric symptoms, or living abilities of VaD patientsrespectively, but more evidence are still in need.(2) Method for calming liver and suppressing yang might improve hyperacti vity of liver yang syndrome scoresinmild to moderate VaD patients, with tolerable safety. No efficient evidence confirmed its effectiveness in improving global impression, cognitive function, living ability or psychiatric symptoms.(3)Method for promoting blood circulation to remove blood stasis might improve cognition, living ability and Chinese medicine syndrome scores of blood stasisin mild to moderate VaD patients, with good safety. No efficient evidence confirmed its efficacy in improving global impression.