Hemorheology is the flow properties of blood. The core role lies in the change of its index before the occurrence of vascular disease [
Studies have shown that ginkgo biloba extract can improve hemorheology [
The computer retrieved the data from China National Knowledge Internet, Wanfang Database, Weipu Network, China Biomedical Literature Database, Cochrane, PubMed, and Clinical Trials databases, and the search was made from the establishment of the database to March 27, 2018. The Chinese search term was “Ginkgo Biloba Dropping Pills”, and the English search terms included “ginkgo”, “ginkgoes”, “yinxingye”, “pill”, and “pills”. The keywords were combined with free words and Boolean logic words (AND, OR, and NOT) were used. The combined method was adjusted according to different databases, all the search strategies were preexperimented several times, and the one with the highest number of documents was finally selected.
The inclusion criteria are as follows: (1) Subjects: randomized controlled trials with unlimited disease types, limited to Chinese and English. (2) Interventions: the control group was treated with placebo or conventional therapy; the treatment group was treated with GBDP or conventional treatment combined with GBDP. (3) Outcome indicators: ① whole blood low cut viscosity, ② whole blood high cut viscosity, ③ plasma viscosity, ④ hematocrit, ⑤ fibrinogen, ⑥ cholesterol, ⑦ low-density lipoprotein, ⑧ high-density lipoprotein, ⑨ triglyceride, and ⑩ adverse reactions; the main outcome indicators include at least one from ①~⑤.
The exclusion criteria are as follows: (1) The test group consists of 3 groups or more. (2) The treatment group adds 2 or more interventions based on the control group. (3) Review, cohort study, case-control, case report, retrospective study, etc. (4) Duplicate documents. (5) Data missing and inaccessible.
The search strategy was developed and searched by two experienced evaluators. According to the preset inclusion and exclusion criteria, the topics and abstracts were read according to a unified process, and the articles were excluded that do not meet the inclusion criteria. Record the first excluded literature and reasons; fatherly obtain the full text of the documents that meet the inclusion criteria, read the full texts to judge whether it met the inclusion criteria, record the second excluded literature and reasons, and finally cross-check the results; the disputed documents were resolved through discussion between the two parties, and they were decided by a third party if not resolved. Extract the data of the final included documents, set the data extraction form, and fill in the data extraction form. The form included the following contents: (1) the patient’s age, gender, duration of the disease, and other baseline data; (2) the author’s name; year of publication; (3) Research background, including research provinces, hospitals, and fund support; (4) research design schemes, comparison methods and types of research, sample size calculation, randomization methods, interventions, intervention courses, number of participants, number of people lost, etc.; (5) outcome indicators.
Using the migration risk assessment tool recommended by the Cochrane Handbook 5.1.0, methodological quality evaluation of the included literature includes the following: (1) random assignment method; (2) covert grouping: (3) blind method; (4) the integrity of the resulting data; (5) selective reporting: (6) other sources of bias. Each aspect was evaluated by “low risk”, “unclear”, and “high risk” and was independently completed by two evaluators and then cross-checked. If the opinions were not unified, the two sides would be discussed and decided. If still undecidable, there would be a ruling by a third party with higher qualifications.
Statistical analysis was performed by the dedicated software Revman 5.3 provided by the Cochrane Collaboration Net. First, the clinical heterogeneity was assessed. If there was no clinical heterogeneity, the chi-square test was used to test the heterogeneity of the results of the relevant literature. If P ≧ 0.10, I2 ≦ 50%, there was no statistical heterogeneity between the results included in the study; the fixed effect model was used for analysis: if p < 0. 10, I2 > 50%, it was considered as statistically different. Then we made an analysis on the heterogeneity sources to determine whether the sensitivity analysis and subgroup analysis were needed, whether random effects models can be used for analysis or not. Descriptive analysis was used if the clinical heterogeneity was too large or the literature was too few to perform meta-analysis. If the result was a binary categorical variable, the relative risk (RR) was used as the analytical statistic, if it was a continuous variable; the mean and standard deviation (WMD) were used as the analytical statistics. The interval estimate was expressed as 95% confidence interval (CI), and a forest map was drawn. Methodological quality evaluation was performed by the bias risk map drawn by Revman 5.3 software. For more than 10 articles on a certain outcome indicator, an inverted funnel plot was used to assess the published bias of the included study.
A total of 539 literature titles were retrieved by computer and manual retrieval methods. The search was carried out according to the corresponding search formulas. A total of 125 English documents were retrieved, and none was eventually included. A total of 414 Chinese literatures were searched and 10 articles in the full text were finally included for meta-analysis after gradually screened. The screening process in the study was shown in Figure
Document screening process.
Finally, 10 randomized controlled trials were included; a total of 1201 cases were reported. There were 608 cases in GBDP group and 593 in control group. The publication period was from 2008 to 2017. Five studies included the main outcome indicators, and one did not indicate the treatment cycle. Basic information for inclusion in the study was shown in Table
Basic information for inclusion in the study.
First author, |
gender (male/female) | Mean age (years) | Intervention | Disease | course | Outcome | |||
---|---|---|---|---|---|---|---|---|---|
T | C | T | C | T | C | ||||
Kuang weiwen 2011 | ukn | ukn | ukn | ukn | GBDP, 300mg, po, tid. Nitroglycerin is prescribed during episode of angina. | Isosorbide nitrate, Aspirin enteric-coated tablets, Nitroglycerin is prescribed during episode of angina. | Unstable angina | 4 w | ③⑤⑥⑦ |
|
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Nong Hanglin |
25/15 | 30/10 | 66.55 | 65.38 | GBDP, 315mg, po, tid. |
Take atorvastatin tablets | Acute cerebral infarction | 4 w | ①②③⑥⑦ |
|
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Wang huigai 2008 | 11/10 | 11/9 | 61 | 60 | GBDP, 180mg, po, tid. |
Routine dehydration, anticoagulation, antihypertensive, anti-infective, and supportive treatment | Cerebral infarction | 1 |
③④⑤ |
|
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Zhang hong 2009 | 36/14 | 30/10 | 66.7 | 67 .1 | GBDP, 180mg, po, tid. |
Compound danshen pain, Aspirin, |
Multi-infarct dementia | 4 w | ①②③④ |
|
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Zhan hong |
18/12 | 16/14 | 42.2 | 41.8 | GBDP, 315mg, po, tid. |
Conventional treatments such as anti-infection, oxygen inhalation, phlegm and asthma relieving. | Chronic obstructive pulmonary disease | 14 d | ① |
|
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Zhou |
86/94 | 72/108 | 72.43 | 74.67 | GBDP, 315mg, po, tid. |
Oral hypoglycemic drugs or insulin injection | Elderly diabetes with atherosclerosis | 12 w | ⑥⑦⑧⑨ |
|
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Tang |
ukn | ukn | 53 | 57 | GBDP, 315mg, po, tid. Fenofibrate, Pioglitazone hydrochloride | Fenofibrate, Pioglitazone hydrochloride | Nonalcoholic fatty liver | 3 m | ⑥⑦⑧⑨ |
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Hong yan 2014 | 66/64 | 31/29 | 70.4 | 70.3 | GBDP, 300mg, po, tid. Amlodipine besylate tablet | Amlodipine besylate tablet | Elderly hypertension | 12 w | ⑥⑦⑧⑨ |
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Wang shengbao2013 | 32/22 | 26/28 | 50 | 53.5 | GBDP, 315mg, po, tid. | Isosorbide nitrate, enteric-coated aspirin | Coronary heart disease | 60 d | ⑦⑧ |
|
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Cai lingqin |
148/30 | 52/26 | 52.8 | 53.1 | GBDP, 300mg, po, tid. Nitroglycerin is prescribed during angina attack. | Nitroglycerin is prescribed during angina attack. | Coronary heart disease angina | ukn | ⑥ |
Note: “T” = “experiment group”, “C” =“control group”, “m”= “months”, “w” =“weeks”, “d”=“days”, and “ukn”= “unknown”.
One of the ten studies was randomized for the order of visits. One study was randomized and two studies were nonequally randomized. Others did not show specific methods. None of the studies described the allocation of concealment methods, and none of the placebo controls were used. Only one report was a single-blind study, seven articles reported adverse reactions, and only one reported shedding and rejection.
Five [
Meta-analysis forest map of plasma viscosity.
Three [
Meta-analysis forest map of the value of high cut blood viscosity.
Three [
Meta-analysis forest map of the value of low cut blood viscosity.
Two [
Meta-analysis forest map of hematocrit.
Three articles [
Meta-analysis forest map of fibrinogen.
Six [
Meta-analysis forest map of triglyceride.
Seven [
Meta-analysis forest map of cholesterol.
Eight [
Meta-analysis forest map of LDL-C.
Seven [
Meta-analysis forest map of HDL-C.
Seven [
Since there were no more than 10 literatures with one outcome indicator, the drawing of inverted funnel diagram had not been carried out.
This study strictly followed the inclusion of exclusion criteria, followed the evidence-based medicine related research norms, and evaluated the meta-analysis of the effects of GBDP on hemorheology. Among the HDL-C results, only one study [
Sensitivity analysis of excluding individual studies.
Meta-analysis forest map after eliminating HDL-C.
The results showed that GBDP can obviously improve blood hemorheology to a certain extent, especially in hematocrit and fibrinogen; it can significantly reduce triglyceride, cholesterol and low-density lipoprotein cholesterol. It may increase the high-density lipoprotein cholesterol index, with mild adverse reactions. Therefore, GBDP can improve blood rheology and blood lipids to some extent and had certain protective effects on vascular function and no obvious adverse reactions were observed.
In many diseases, the increase of hemorheology and lipid index indicates that blood is in a thick and viscous state, which is prone to blood stasis. In view of “blood stasis”, the traditional Chinese medicine (TCM) adopts the method of activating blood and removing blood stasis. Current research shows that most of TCM for activating blood circulation have certain effect in the blood rheology, blood viscosity, platelet function, anticoagulation, protecting vascular endothelial cells, regulating blood lipid, etc., which has been widely applied in the treatment of cardiovascular diseases of its unique advantages in reducing the incidence of ischemic cerebrovascular disease, mortality and morbidity. What is more, compared with other drugs, the adverse reaction is small and relatively safe and has potential application prospect in the aspect of prevention, treatment, and rehabilitation [
Ginkgo biloba extract has complex components; more than 160 kinds have been found so far, and its active components are mainly ginkgo flavonoids and ginkgo lactolides. According to the different extraction solvent, there are mainly three preparations of GBDP, ginkgo biloba extract tablets, and ginkgo ketone ester drop pills. The content of flavanols in GBDP is significantly higher than the other two preparations [
Currently, there is no systematic review or meta-analysis of the effects of GBDP on hemorheology, only one systematic review on the effect of ginkgo biloba extract on hemorheology, which shows that ginkgo biloba extract can reduce blood and plasma viscosity and improve hemorheology in early diabetic nephropathy [
However, there are some limitations in the inclusion of this study: (1) Insufficient search, only Chinese and English literature are restricted, yet other languages are not searched. (2) The quality of clinical trials included is low, and 7 studies do not describe the method of generating random sequences. The hiding of the whole studies’ allocation program was not described, and sufficient information was not given to judge the quality of the studies. (3) No subgroup analysis of age and gender, the results lack certain representativeness. (4) The inconsistent treatment methods in the control group and the difference in drug dosage may have an impact on the evaluation of efficacy and safety. (5) The in-homogeneity of disease and treatment included in the study have not been able to evaluate the long-term efficacy. (6) Other hemorheology outcome indicators, such as erythrocyte aggregation coefficient, platelet adhesion, and platelet aggregation function, have not been included in hemorheology, so results need to be further improved.
In summary, in patients with hemorheology and dyslipidemia, GBDP can be taken individually or additionally, especially suitable for those with high hematocrit, fibrinogen, and cholesterol. To a certain extent, it plays a role in preventing and treating cardiocerebral and renal vascular diseases. However, our results are based on published studies, the number of included studies is small, and the quality is poor, which may lead to low credibility of conclusions. Currently blood rheology has not reached universal popularity in clinical applications, but there are good research prospects from this paper. Therefore, in the future, more large-scale, multicenter randomized controlled clinical trials and researches on related mechanisms should be implemented in a scientifically designed manner, more outcome indicators should be selected, longer treatment and follow-up observation should be conducted, and better clinical trial evidence should be obtained to fatherly verify the efficacy and safety of GBDP in hemorheology and vascular diseases.
The data supporting this systematic review and meta-analysis are from previously reported studies and datasets, which have been cited.
The authors declare that there are no conflicts of interest.
Hong Chen, Cihang Zhou, and Mingwei Yu contributed equally to this work.
This work was supported by the National Natural Science Foundation of China Youth Fund Project (81603579), the Beijing Science and Technology Project (no. D161100005116005), the National Natural Science Foundation (81774146), Beijing Science and Technology Nova (Z1511000003150125), and Yanjing School’s Innovative “Fist” Project.