Butylphthalide combined with donepezil for the treatment of vascular dementia: a meta-analysis

Abstract

Objective

To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia.

Methods

Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software.

Results

Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment.

Conclusion

Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.

Introduction

Vascular dementia is a neurocognitive disorder that represents clinically significant cognitive impairment and is related to various cerebrovascular diseases including atherosclerosis, infarction, and hemorrhage. ¹ It is the second most common cause of dementia, after only Alzheimer’s disease, and is a major health concern worldwide. Vascular dementia accounts for roughly 15% to 20% of dementia cases in North America and Europe, with a somewhat higher estimate of approximately 30% in Asia. ² Because of the increasing age of the global population, the number of vascular dementia patients is expected to increase each year, which will cause a great economic burden in all countries worldwide.

The main clinical features of vascular dementia include cognitive impairment, psycho-behavioral symptoms, and a decline in daily living abilities. ³ Currently, cholinesterase inhibitors and galantamine are commonly used to treat vascular dementia. Because of the modest cognitive improvements, controversy exists regarding the recommendation grade for these drugs in medical guidelines. ⁴ Notably, cholinesterase inhibitors may cause more intolerable adverse reactions with large doses. For example, 10 mg of donepezil has a significantly higher risk of discontinuation related to adverse reactions than a 5-mg dose of donepezil. ⁵ In China, traditional Chinese medicine is one of the most important supplementary treatments for patients with vascular dementia. ⁶ Many randomized controlled trials (RCTs) have shown that Chinese patent medicines or Chinese herbal extracts can further improve the cognitive abilities and dementia symptoms of vascular dementia patients in combination with donepezil treatment.^7–11 However, the recommendation grade of traditional Chinese medicine in clinical guidelines is low because of their complex components or unclear pharmacological mechanism. ¹²

Butylphthalide is a pure compound extracted from Apium graveolens Linn that was approved by the China Food and Drug Administration in 2002 for the treatment of ischemic stroke because of its protective effects against cerebral ischemia. ¹³ In recent years, increasing numbers of RCTs have shown that butylphthalide can further improve the behavioral abilities and dementia symptoms of vascular dementia patients, particularly when combined with donepezil treatment.^14–22 However, these studies do not provide guidance for its clinical application. Our study aimed to systematically evaluate the efficacy and safety of butylphthalide combined with donepezil for the treatment of vascular dementia and its potential pharmacological mechanisms through a meta-analysis to provide an objective and reliable reference for the clinical use of butylphthalide.

Methods

Study registration and reporting guidelines

The protocol for this meta-analysis was registered on INPLASY, registration number INPLASY202310057 (URL: https://inplasy.com/inplasy-2023-1-0057/). This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ²³ Ethics approval was not required for this meta-analysis, and the privacy of patients was protected.

Search strategy

RCTs of butylphthalide combined with donepezil for treatment of vascular dementia were collected from the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical (VIP), Wan Fang, and China Biology Medicine databases. The search used a combination of subject words and free words, and two reviewers (Puqing and Jingwen) independently traced the references of the included literature (from database inception to 29 November 2022) to supplement the acquisition of relevant literature. The search terms included vascular dementia/vascular cognitive impairment, 3-n-butylphthalide, donepezil, and randomized controlled trial/RCT. The search strategy for the PubMed database is shown as an example in Appendix 1.

Inclusion and exclusion criteria

The inclusion and exclusion criteria were mainly based on the PICOS principle, which specifically refers to patients, intervention, comparison, and study style.

The inclusion criteria were as follows: (1) Patients: The patients were diagnosed with vascular dementia according to the “Chinese Guidelines for Diagnosis and Treatment of Dementia and Cognitive Impairment (I): Dementia and its classification and diagnostic criteria (2018)” ²⁴ and “Guidelines for Diagnosis and Treatment of vascular cognitive Impairment in China (2019)”. ²⁵ (2) Intervention: The experimental group patients were given donepezil tablets in combination with butylphthalide soft capsules (0.2 g, three times a day); the control group patients were only given donepezil tablets, usually 5 mg once every day (15 mg for some severe patients). There was no limit to the course of treatment, which was usually approximately 3 months. Other basic treatment measures were similar between the experimental and control groups. (3) Outcomes: The primary outcomes included the total effectiveness rate and incidence of adverse events. The total effectiveness was defined as a greater than 12% improvement in cognitive function and behavior ability assessment according to the Mini-Mental State Examination (MMSE). Adverse events referred to any increases in transaminase levels, emergence of nausea, discomfort in the stomach, nasal obstruction, insomnia, or rashes in patients during the treatment. The secondary outcomes included the MMSE, abilities of daily living (ADL), and Montreal Cognitive Assessment (MoCA) scores and blood levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and superoxide dismutase (SOD). (4) Study style: Blinded or non-blinded RCTs were included, including Chinese and English literature.

The exclusion criteria were as follows: (1) Studies that were not RCTs, such as animal-related studies, case reports, reviews, letters, or editorials; (2) RCTs that did not meet the PICOS principle; (3) Studies with incomplete or incorrect data; (4) The study contained republished data.

Data extraction

An information extraction table was jointly created by two researchers (Puqing and Jingwen). The candidate studies were independently evaluated and extracted. Disagreements were resolved by negotiation of two researchers, or a third researcher assisted in judgment. For studies lacking data, we attempted to contact the original author. The extracted data consisted of the following information: basic study information, including the first author’s name and publication year; basic characteristics of patients, such as the sample size, age, sex, type of disease, and disease course; elements of bias risk assessment; and details of the interventions, course, and outcomes.

Risk of bias assessment

The bias risk assessment was carried out independently by two reviewers according to the bias risk assessment tool of the Cochrane Handbook for Systematic Reviews of Interventions (v6.3), ²⁶ and the results were cross-checked. In the case of any disagreement, the results were discussed and resolved.

Statistical analysis

We used RevMan5.4 statistical software (The Cochrane Collaboration, London, UK) to perform the meta-analysis. Binary variable outcomes were compared using the relative risk (RR), while continuous variable outcomes were compared using the mean difference (MD), and all were expressed with the 95% confidence interval (CI). The heterogeneity of the included studies was tested. If I² < 50% and P > 0.1, there was considered no heterogeneity, and the fixed effect model was chosen for the meta-analysis. If 50% ≤ I² ≤ 75% and P < 0.1, there was considered mild to moderate heterogeneity. A heterogeneity analysis was carried out to identify the source of heterogeneity, and the random effect model was used for the meta-analysis. If I² > 75%, statistical heterogeneity was considered to exist among the studies, and therefore a meta-analysis was inappropriate. In this situation, a descriptive analysis was considered.

Results

Study inclusion

A total of 155 studies were searched, including 154 Chinese studies and one English study. After importing the data into Endnote software (Thomson Scientific, Philadelphia, PA, USA), 93 duplicate studies were removed and 62 remained. After reading the title and abstract of the articles, 26 studies were eliminated, and 36 remained. Seventeen studies published before 2018 were excluded from the meta-analysis and 19 remained. After reading the full text, six articles with incomplete data, one article with repeated data, two articles with incorrect data, and one non-RCT study were excluded. Finally, nine RCTs (one English) were included, encompassing 1024 patients. The studies screening process is shown in Figure 1.

Figure 1.

Study screening flow chart. CNKI, China National Knowledge Infrastructure; CBM, China Biology Medicine; VIP, Chinese Science and Technology Periodical Database; RCT, randomized controlled trial.

Basic characteristics

All of the included RCTs were published between 2018 and 2022, with a sample size ranging from 39 to 107 Chinese patients diagnosed with vascular dementia. The patients in the experimental group received butylphthalide combined with donepezil, and patients in the control group received donepezil alone. A summary of the included studies is shown in Table 1.

Table 1.

Characteristics of the included studies.

AuthorYear	Sample size		Intervention measures		Intervention time	Outcomes
	Experimental	Control	Experimental	Control
Wang [ 14 ] 2019	62	62	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	3 months	(1) (2) (3) (4) (8)
Wang [ 15 ] 2022	50	50	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	3 months	(1) (2) (3) (4)
Xu [ 16 ] 2018	39	39	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	3 months	(1) (2) (3) (4)
Xu [ 17 ] 2019	60	60	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	90 days	(1) (2) (4)
Wang [ 18 ] 2020	48	48	Butylphthalide 0.2 g tid + Donepezil 5 mg (4 weeks)/10 mg (4 weeks) qd	Donepezil 5 mg (4 weeks)/10 mg (4 weeks) qd	8 weeks	(1) (2) (5) (6) (7)
Zhou [ 19 ] 2020	46	46	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	3 months	(1) (2) (3) (5) (6) (9)
Cui [ 20 ] 2021	49	49	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	90 days	(1) (3) (4) (8)
Qiu [ 21 ] 2022	107	107	Butylphthalide 0.2 g tid + Donepezil 5–15 mg qd	Donepezil 5–15 mg qd	24 weeks	(1) (2) (3) (4) (6) (7) (8) (9)
You [ 22 ] 2022	51	51	Butylphthalide 0.2 g tid + Donepezil 5 mg qd	Donepezil 5 mg qd	12 weeks	(1) (2)

(1) Clinical efficiency; (2) Adverse events; (3) Mini-Mental State Examination score; (4) abilities of daily living score; (5) Montreal Cognitive Assessment score; (6) interleukin-6; (7) tumor necrosis factor-α; (8) superoxide dismutase; (9) homocysteine. Abbreviations: tid, three times daily; qd, once daily.

Risk of bias assessment

The bias risk assessment included the following seven items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. All nine studies were RCTs classified as low risk regarding random sequence generation, among which six referred to a “random digital table” and one adopted a “random lottery”. One double-blind study and another single-blind study were rated as low risk, while others without specific details of the blinding method were rated as unclear risk regarding blinding of participants and personnel. All nine studies had complete outcome data and were classified as low risk for incomplete outcome data; those with no selective reporting were ranked as low risk, and those that did not describe other bias were rated as unclear risk. The risk bias assessment results are shown in Figure 2.

Figure 2.

Risk of bias graph.

Primary outcomes of the meta-analysis

Clinical efficacy

Nine studies including 1024 patients reported the total clinical efficacy. There was no heterogeneity among these studies (P = 0.95, I² = 0%); therefore, the fixed effect model was chosen for the meta-analysis. The results demonstrated that the total clinical efficiency of butylphthalide combined with donepezil for vascular dementia was significantly better than that of donepezil alone (RR = 1.24, 95% CI [1.17, 1.31], P < 0.00001) (Figure 3).

Figure 3.

Forest plot of the meta-analysis comparing the clinical efficacy between butylphthalide combined with donepezil (experimental group) and butylphthalide alone (control group) using the fixed effect model. CI, confidence interval; M-H, Mantel Haenszel method.

Adverse events

Eight studies reported adverse events, and there was no heterogeneity among these studies (P = 0.62, I² = 0%). The fixed effect model was used for the meta-analysis. The result showed that the adverse event incidence was not significantly different between the butylphthalide combined with donepezil and the donepezil group of vascular dementia patients (RR =1.39, 95% CI [0.91, 2.14], P = 0.13) (Figure 4).

Figure 4.

Forest plot of the meta-analysis comparing the adverse events between butylphthalide combined with donepezil (experimental group) and butylphthalide alone (control group) using the fixed effect model. CI, confidence interval.

Secondary outcomes of the meta-analysis

MMSE, ADL, and MoCA scores

Seven studies used the MMSE score to assess the cognitive function of vascular dementia patients, and a moderate degree of heterogeneity was found among these studies (P = 0.001, I² = 73%). A sensitivity analysis was conducted, and heterogeneity was significantly reduced after the studies by Cui ²⁰ and You ²² (P = 0.16, I² = 40%) were excluded. Then, the fixed effect model was adopted to conduct a meta-analysis of the other five studies, including 304 patients. The results showed that butylphthalide combined with donepezil had a better effect than donepezil alone in improving the MMSE scores of patients with vascular dementia (MD = 3.61, 95% CI [3.26, 3.96], P < 0.00001) (Figure 5a). Six studies reported the ADL score to assess the activities of daily living in 600 vascular dementia patients. A high degree of heterogeneity was found across the studies (P = 0.001, I² = 73%). A sensitivity analysis was conducted by excluding the studies one by one. No change in heterogeneity was noted, indicating that the result was stable and available. The random effect model was used for the meta-analysis, and the result showed that the improvements in the ADL scores in vascular dementia patients treated with butylphthalide combined with donepezil were greater than in those treated with donepezil alone (MD = 15.31, 95% CI [10.60, 20.02], P < 0.00001) (Figure 5b). Two studies used the MoCA score to assess the cognitive function of vascular dementia patients, and no heterogeneity was found among the studies (P = 0.72, I² = 0%). A meta-analysis using a fixed effect model indicated that vascular dementia patients treated with butylphthalide combined with donepezil showed greater improvements in MoCA scores than those treated with donepezil monotherapy (MD = 2.38, 95% CI [2.05, 2.71], P < 0.00001) (Figure 5c).

Figure 5.

Forest plot of the meta-analysis comparing the cognitive and behavioral abilities of patients between those treated with butylphthalide combined with donepezil (experimental group) and those treated with butylphthalide alone (control group): (a) Mini-Mental State Examination score, (b) abilities of daily living score, and (c) Montreal Cognitive Assessment score. CI, confidence interval; SD, standard deviation; IV, inverse variance method.

Blood levels of IL-6, TNF-α, and SOD

Three studies reported IL-6 values and had a high degree of heterogeneity (P < 0.00001, I² = 98%). A sensitivity analysis showed that the heterogeneity was significantly reduced after the study You ²² was removed (P = 0.46, I² = 0%). A meta-analysis using a fixed effect model demonstrated that butylphthalide combined with donepezil had a stronger inhibitory effect on the IL-6 level than donepezil alone in vascular dementia patients (MD = −12.92, 95% CI [−18.24, −7.61], P < 0.00001) (Figure 6a). Two studies reported TNF-α values and had no heterogeneity (P = 0.69, I² = 0%). A meta-analysis using a fixed effect model indicated that butylphthalide combined with donepezil had a greater inhibitory effect on the TNF-α level than donepezil alone in vascular dementia patients (MD = −34.74, 95% CI [−40.52, −28.95], P < 0.00001) (Figure 6b). The SOD value was reported in three studies, with a high degree of heterogeneity (P < 0.00001, I² = 98%). A sensitivity analysis showed that heterogeneity was significantly reduced after the study by Wang ¹⁸ was removed (P = 0.35, I² = 0%). The fixed effect model was adopted for the meta-analysis, and the results indicated that butylphthalide combined with donepezil could better increase the serum SOD level than donepezil alone in vascular dementia patients (MD = 20.18, 95% CI [17.17, 23.19], P < 0.00001) (Figure 6c).

Figure 6.

Forest plot of the meta-analysis comparing the lab test items of patients between those treated with butylphthalide combined with donepezil (experimental group) and those treated with butylphthalide alone (control group): (a) blood level of interleukin-6, (b) blood level of tumor necrosis factor-α, and (c) blood level of superoxide dismutase. CI, confidence interval; SD, standard deviation.

Discussion

This meta-analysis showed a significant improvement in the total efficacy rate of combined butylphthalide and donepezil treatment without a significant difference in adverse events such as nausea, vomiting, dizziness, fatigue, insomnia, drowsiness, or other mild adverse reactions. This result was consistent with those of previous meta-analyses.^27–28 No scoring tool has been designed specifically to measure cognitive ability in vascular dementia patients. Thus, the assessment tools for cognitive function, such as the MMSE, ADL, and MoCA, that were initially designed for Alzheimer’s disease patients are commonly used in vascular dementia studies.^29–31 Five RCTs indicated improvement in the patients’ MMSE scores, six RCTs showed improvement of ADL scores, and two RCTs indicated improvement in the patients’ MoCA scores. The blood level of IL-6 represents a useful biomarker to differentiate people with vascular dementia from those with Alzheimer’s disease and to predict a future vascular dementia risk in healthy subjects. ³² TNF-α is involved in the neuroinflammation observed in the brains of patients with vascular dementia, although it does not have the same diagnostic significance as IL-6. ³³ SOD is an antioxidant substance, and a decrease in SOD content is a sign of antioxidant capacity reduction in tissues, which is significantly correlated with the degree of dementia. Thus, it can be used as a risk factor of vascular dementia prediction and measure of efficacy evaluation. ³⁴ In this study, two RCTs showed inhibition of IL-6 production, two RCTs indicated a reduction in blood levels of TNF-α, and two RCTs showed increased production of SOD.

Pharmacological studies of butylphthalide have shown that it can directly cross the blood–brain barrier, ³⁵ improve mitochondrial function and the structural integrity of injured nerve cells under hypoxic conditions,^36–37 activate mitochondrial ATPase and antioxidant enzymes, inhibit the inflammatory response and apoptosis in nerve cells, ³⁸ enhance the level of cerebral nitric oxide, boost ischemic microcirculation, resist platelet aggregation and cerebral thrombosis, and advance vascular repair in patients with vascular dementia.^39–40 The clinical effects of butylphthalide displayed in biochemical examinations matched its pharmacological mechanisms of anti-inflammatory, antioxidant, and antiplatelet effects.

Our study included the most recently published RCTs and excluded RCTs published before 2018, which were all included in previously published meta-analyses. Our study mainly focused on the clinical efficacy and safety of butylphthalide on the basis of donepezil use instead of observing donepezil on the basis of butylphthalide use. Therefore, in the literature screening process, the intervention measure of butylphthalide combined with donepezil was used for the experimental group and donepezil treatment alone was used for the control group. Some RCTs that did not meet the inclusion criteria were excluded, and the clinical efficacy indicators in our study were well-defined. The blood levels of IL-6, TNF-α, and SOD were analyzed to identify the clinical efficacy of butylphthalide based on the pathophysiological mechanism of vascular dementia.

Our meta-analysis had several limitations. First, all of the studies were conducted in China, and the patients included in the studies were all Chinese, so the meta-analysis had regional and ethnic limitations. Second, the quality of the included RCTs was not high. Although all studies were RCTs, the randomized methods were not elaborated in detail. Only one of these studies was double-blind. No study described whether the analysis of outcome indicators was performed using a blinded method. Third, the sample size in each study was small, with approximately 50 vascular dementia patients in the experimental or control group in a single RCT. Fourth, there were differences in the disease courses of vascular dementia patients (from months to years), intervention times (8 , 12, and 24 weeks), and outcome indicators (some outcome indicators appeared only in two studies) among the included RCTs. Fifth, there were no studies that compared the treatment cost of combining butylphthalide with donepezil versus donepezil alone.

Conclusion

This study showed that for patients with vascular dementia, butylphthalide combined with donepezil can exhibit increased total clinical efficacy, enhance cognitive function, and improve some related laboratory test indicators without a significant increase in adverse events. However, higher-quality and larger-scale RCTs are still needed to compare the advantages and disadvantages of butylphthalide and donepezil combination therapy. Future clinical trials should overcome the limitations of this study described above, thus allowing more reliable evidence-based treatment decisions by healthcare practitioners.

Appendix 1: The randomized controlled trial search strategy for the PubMed database through 29 November 2022

Database	Search strategy
PubMed	#1 “Dementia, Vascular” [Mesh]
	#2 Vascular dementia OR vascular dement* OR vascular cognitive impairment*
	#3 VaD OR VCI
	#4 #1 OR #2 OR #3
	#5 “3-n-butylphthalide” [Supplementary Concept]
	#6 DL-3-n-butylphthalide OR l-NBP cpd OR N-butylphthalide OR butylphthalide OR (S)-(-)-3-butylphthalide OR NBP
	#7 #5 OR #6
	#8 “Donepezil”[Mesh]
	#9 Donepezilium Oxalate Trihydrate OR E 2020 OR E2020 OR Donepezil Hydrochloride OR 1-Benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine hydrochloride OR Aricept
	#10 #8 OR #9
	#11 #7 AND #10
	#12 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR clinical trials as topic[mesh:noexp] OR randomly[tiab] OR trial[ti] NOT (animals[mh] NOT humans [mh]))
	#13 #4 AND #11 AND #12