Effects of Yangxue Qingnao Granules on chronic cerebral circulation insufficiency: a randomized, double-blind, double-dummy, controlled multicentre trial


Dr Lianming Liao PhD, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Huatuo Road, No1, Fuzhou 350108, Fujian, China. Email: llm@fjtcm.edu.cn; Prof Renmin Yang MD, Institute of Neurology, Affiliated Hospital, Anhui College of Traditional Chinese Medicine; Changjiang Road, no. 357, Hefei 230031, Anhui, China. Email: yrm724120@sina.com


Background:  There is a great deal of interest in traditional Chinese medicine as a treatment for chronic cerebral circulation insufficiency (CCCI). In the present study, we evaluated the efficacy and safety of Yangxue Qingnao Granules (YXQNG) as a monotherapy in patients with CCCI.

Methods:  From July 2007 to May 2010, 273 patients with CCCI at nine centres in China were randomly assigned to receive either YXQNG with nimodipine placebo (n= 140, 12 g/day) or nimodipine with YXQNG placebo (n= 133, 30 mg/day) for 8 weeks. The primary end points after 8 weeks of treatment were changes from baseline in severity of headache, heavy-headed feeling, dizziness and sleep disorder.

Results:  The mean baseline levels of headache, heavy-headed feeling, dizziness and sleep disorder were comparable between the two groups. Both therapies significantly improved these symptoms after 8 weeks of treatment (P < 0.001). Compared with nimodipine therapy, YXQNG resulted in similar reductions in these symptoms. No adverse effects were observed in the YXQNG group.

Conclusions:  These data demonstrate that YXQNG as a monotherapy were as effective as nimodipine monotherapy in improving the symptoms of CCCI. It is well-tolerated and may have an important place in the management of this condition. Whether a combination of these two medicines will increase therapeutic efficacy deserves further clinical investigation.


Chronic cerebral circulation insufficiency (CCCI) is common in the elderly and is considered to contribute to later development of cerebral infarction, vascular dementia and Alzheimer's disease.1,2 The elderly with CCCI usually complain of symptoms including headache, heavy-headed feeling, dizziness, cognitive impairment, depressive and sleep disorders.3 Although magnetic resonance imaging often shows no marked anatomical cerebral lesion or abnormality, cerebral circulatory examination can reveal reduced cerebral blood flow. Animal studies have shown that CCCI may cause white matter lesions, cognitive impairment and memory impairment, which is often observed in patients with ischemic cerebrovascular diseases.4–10

Currently, no effective clinical treatment is available for CCCI. Yangxue Qingnao Granules (YXQNG), which roughly translates to granules to tonify blood and clear liver heat, were approved by the Chinese health authorities in 1997 and has been used to treat headaches,11,12 insomnia,13,14 vertigo,15 and dizziness due to blood deficiency and excessive liver yang, a pattern of symptoms defined by traditional Chinese medicine. It has been widely used for patients with these symptoms as well as for patients with vascular dementia.16 In line with these reports, YXQNG were suggested for treatment of CCCI.17 Although this initial study showed that YXQNG reduced symptoms in patients with CCCI, the number of patients enrolled was small and the trial was nonrandomized.17

To further evaluate the efficacy of YXQNG for CCCI-related symptoms, we conducted a multicentre, double-blind, randomized, controlled clinical trial to compare the benefits of YXQNG with nimodipine. We hypothesized that at the end of the 8-week intervention period, patients in the YXQNG group would have a great improvement in CCCI-related symptoms, especially headaches.


Men and women (aged ≥30 years) with a diagnosis of CCCI were enrolled in the study. The diagnostic criteria for CCCI were established according to a previous publication.18 They included: (i) presence of one or more of these symptoms: dizziness, especially positional dizziness, vertigo, heavy-headed feeling and/or headache; (ii) presence of cerebrovascular stenosis, especially fundus oculi arteriosclerosis, revealed by transcranial Doppler; and (iii) absence of organic cerebrovascular diseases judged with computed tomography or magnetic resonance imaging.

Exclusion criteria included clinical or radiological evidence of neurodegenerative disorders (e.g. vascular dementia, Parkinson's disease). Patients with major depression or other psychiatric disorders were excluded. Patients who had experienced a cerebral infarction were excluded, as were those with clinically relevant hepatic, pulmonary, gastrointestinal or life-threatening disease. Additional reasons for exclusion included pregnancy and a history of alcohol or drug abuse.

Before being enrolled, patients provided written informed consent to participate in the study, which was conducted according to the Declaration of Helsinki (2008). The protocol was reviewed and approved by the designated human subjects review board at each participating site.

Study design

This was an 8-week multicentre, double-blind, double-dummy, randomized, controlled, parallel-group study that ran from July 2007 until May 2010. The trial aimed to compare the efficacy and safety of YXQNG and nimodipine in alleviating symptoms in CCCI patients. Patients were assigned to one of two treatment groups by a computer-generated randomization protocol. Patients received YXQNG with nimodipine placebo (n= 140) or nimodipine with YXQNG placebo (n= 133) for 8 weeks.

Therapeutic methods

YXQNG were provided by Tianjin Tianshili Pharmaceutical Co., Ltd (Tianjin, China). The recipe for YXQNG includes Chinese angelica root, Ligusticum chuanxiong rhizome, prepared Rehmannia root, white peony root, cassia seed, pearl shell layer and prunella spike. One 4-g package of YXQNG was given to subjects three times a day. One 10-mg nimodipine was given three times per day. Placebo of both medications was provided by Tianjin Tianshili Pharmaceutical Co., Ltd.

Psychometric evaluations and neurological examinations, laboratory determinations, and measurements of vital signs were performed at baseline and at week 8 (together with checks for medication compliance and adverse events).

Efficacy assessments

The primary end points included four outcome measures after 8 weeks of treatments: changes from baseline in severity of headache, heavy-headed feeling, dizziness and sleep disorder. Headache severity was recorded on an 11-point numerical rating scale anchored at zero for no pain and 10 for the worst imaginable pain. The intensity of dizziness and sleep disorder was graded on a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe).

In each centre, one clinician (rater) who was unaware of the subject's treatment would perform outcome measurements. At least one clinician in each centre provided treatment and recorded any adverse events. To establish interrater and intrarater reliability, raters from all centres were trained before the trial began. Cohen's kappa coefficients were used to determine intrarater and interrater reliability for all rating scales. Intrarater reliability was established by the raters using 10 subjects who were reassessed in random order. Interrater reliability was established using five subjects who were assessed by the 10 raters and an experienced clinician. Cohen's kappa for intrarater reliability was established at 0.825. The kappa for interrater reliability of the 10 raters and the experienced clinician was established at 0.611.

Safety assessments

The safety and tolerability of study medication were assessed by comparing rates of discontinuation and treatment-related adverse events between treatment groups, as well as changes from baseline in laboratory test values and vital signs and changes on physical examination.

Statistical analysis

Analysis of efficacy was based on the intent-to-treat population, which included all patients who received at least one dose of study medication, had baseline data and had at least one post-baseline efficacy assessment. All patients who received at least one dose of study medication were included in the safety analysis.

Baseline demographic characteristics were analyzed with the Fisher's exact test, χ2 test or Wilcoxon signed-rank test (for categorical measures), or t-test (for continuous measures). Categorical efficacy assessments were analyzed with a Cochran–Mantel–Haenszel test. Significance was set at P≤ 0.05 for all statistical tests.



A total of 289 patients from nine hospitals were enrolled in the study and randomized for treatment. The number of patients ranged from 10 to 40 per centre (median, 38), and 273 (94.46%) completed the study and were used for analysis.

The YXQNG and nimodipine treatment groups were well matched with respect to baseline demographics, medical history, presence of cardiovascular risk factors and baseline assessment scores (Table 1).

Table 1. Patient demographics and baseline characteristics
VariableYangxue Qingnao GranulesNimodipine P-value
n= 140 n= 133
Age, mean ± SE (range) (years)61.87 ± 10.48 (38–84)61.95 ± 10.37 (36–90)0.947
Body weight (kg)64.39 ± 9.0664.79 ± 8.770.589
Hypertension (n (%))90 (64.29)90 (67.67)0.555
Hypertension, mean ± SE (range) (years)7.34 ± 6.45 (1.00–30.00)7.21 ± 6.22 (1.00–30.00)0.959
Smokers (n (%))27 (19.29)36 (27.07)0.127
Years of smoking, mean ± SE (range)18.52 ± 12.66 (0.00–50.00)22.82 ± 12.84 (0.00–40.00)0.122
Hypercholesterolemia33 (23.57)25 (18.80)0.335
Headache stage rating at baseline (n (%))   
 Grade 0000.603
 Grade 128 (20.00)31 (23.31)
 Grade 28 (5.71)9 (6.77)
 Grade 315 (10.71)9 (6.77)
 Grade 422 (15.71)16 (12.03)
 Grade 519 (13.57)22 (16.54)
 Grade 626 (18.57)16 (12.03)
 Grade 77 (5.00)20 (15.04)
 Grade 810 (7.14)8 (6.01)
 Grade 94 (2.86)1 (0.75)
 Grade 101 (0.71)1 (0.75)
Dizziness rating at baseline (n (%))   
 Mild54 (38.57)40 (30.08)0.086
 Moderate79 (59.40)82 (61.66)
 Severe7 (5.00)11 (8.27)
Heavy-headed feeling at baseline (n (%))   
 Yes49 (35.00)33 (24.81)0.066
 No91 (65.00)100 (75.19)
Sleep disorder at baseline (n (%))   
 Mild97 (69.29)82 (61.65)0.127
 Moderate30 (21.42)42 (31.58)
 Severe13 (9.29)9 (6.77)

The mean overall compliance with study medication was 93.57% (131/140) in the YXQNG group and 92.48% (123/133) in the nimodipine group (P= 0.723). The percentage of subjects taking concomitant medications was 25.71% (36/140) in the YXQNG group and 24.06% (32/133) in the nimodipine group (P= 0.752). Antihypertensive agents were among the most commonly taken medications.

Primary efficacy analyses

Patients treated with YXQNG demonstrated significant improvements, compared to their baseline values, in severity of headache (P= 0.000), heavy-headed feeling (P= 0.000), dizziness (P= 0.000) and sleep disorder (P= 0.000) after 8 weeks. Similarly, patients treated with nimodipine demonstrated significant post-baseline improvements in severity of headache (P= 0.000), heavy-headed feeling (P= 0.000), dizziness (P= 0.000) and sleep disorder (P= 0.000). Improvements were similar between the two groups (Table 2).

Table 2. Efficacy measure outcomes in Yangxue Qingnao Granules (YXQNG) and nimodipine-treated patients at week 8
VariableYXQNGNimodipine P-value
n= 140 n= 133
Headache stage rating (n (%))
 Grade 0000.052
 Grade 155 (39.29)60 (45.11)
 Grade 239 (27.86)39 (29.32)
 Grade 318 (12.86)18 (13.53)
 Grade 415 (10.71)8 (6.01)
 Grade 58 (5.70)6 (4.51)
 Grade 65 (3.57)2 (1.50)
 Grade 700
 Grade 800
 Grade 900
 Grade 1000
Dizziness rating at baseline (n (%))
 Mild117 (83.57)101 (75.94)0.166
 Moderate21 (15.00)30 (22.56)
 Severe2 (1.43)2 (1.50)
Heavy-headed feeling at baseline (n (%))
 Yes108 (77.14)101 (75.94)0.823
 No32 (22.86)32 (24.06)
Sleep disorder at baseline (n (%))
 Mild131 (93.57)125 (93.98)0.528
 Moderate9 (6.43)8 (6.02)

Safety analyses

There was a low incidence of adverse events in both treatment groups; the rates were 8.57% (12/140) for the YXQNG group and 6.02% (8/133) for the nimodipine group (P= 0.245). Generally, adverse events were mild to moderate in intensity, were transient and resolved without the need to discontinue study medication. The adverse events most commonly reported were those affecting the digestive system and the nervous system (Table 3).

Table 3. Adverse events
 YXQNGNimodipine P-value
  1. YXQNG, Yangxue Qingnao Granules.

Digestive system (n (%))4 (2.86)5 (3.76)0.418
Nervous system (n (%))5 (3.57)0 (0)
Cardiovascular system (n (%))1 (0.71)0 (0)
Urinary system (n (%))1 (0.71)0 (0)
Skin reaction (n (%))0 (0)2 (1.50)
Others (n (%))1 (0.71)1 (0.75)
Total12 (7.86)8 (6.02)

No clinically meaningful changes from baseline were observed in vital signs, physical examination findings, clinical chemistry, haematology, or urinalysis tests in any of the treatment groups. Safety and tolerability were similar between the two groups.


This randomized, controlled trial shows that YXQNG are potentially a useful therapy for patients with CCCI. The effect was evident after 8 weeks of treatment, with improvements in headaches, heavy-head sensation, dizziness and sleep disorder, which also improved the subjects' quality of life. No serious adverse events were reported, indicating that YXQNG are a safe therapy for patients, even elderly patients, with CCCI.

Our results are consistent with those of a previous, nonrandomized trial of YXQNG for CCCI,17 as well as with the findings of other studies showing the benefits of YXQNG with regard to headache,11,12 insomnia,13,14 vertigo,15 and vascular dementia.16

The biologic mechanisms by which YXQNG might affect the clinical manifestations of CCCI remain unknown. As a complex, multicomponent recipe, YXQNG may act through many mechanisms to improve health outcomes. Li reported that YXQNG could lower blood viscosity and enhance cerebral blood flow rate.19 In a chronic cerebral hypoperfusion model, Xiong et al. demonstrated that cognitive impairment induced by chronic cerebral hypoperfusion could be ameliorated by YXQNG treatment. Treatment with YXQNG resulted in significant reduction in apoptosis and significant increases in total antioxidant capacity and choline acetyltransferase activities in both the hippocampus and the cortex.20 YXQNG may prevent neurons in the hippocampal CA1 region from apoptosis after global ischemia reperfusion brain injury by inhibiting expression of caspase-3 and glutamate synthase.21 In studies involving mice, YXQNG reduced the spontaneous movement of mice and enhanced the sedative effects of pentobarbital sodium, as indicated by their prolonged sleeping time when YXQNG were given in combination with pentobarbital sodium.22 YXQNG also had analgesic effects in mice that were induced by pressure and acetic acid, although the underlying mechanism is unclear,23 and it can increase their cerebral blood flow.23 Evidence indicates that YXQNG can decrease the plasma viscosity, blood viscosity at the low or high shear rate, and the erythrocyte aggregation index, which is thought to explain why YXQNG can alleviate headaches in migraine patients.24

Our study had some advantages. First we used a double-blind, double-dummy study design. This minimized the influence of pre-existing beliefs and expectations with respect to traditional Chinese medicine (e.g. the placebo effect), as traditional Chinese medicine is widely used in China and is believed to be effective in treating various diseases. To ensure that the quality of the blind was maintained, capsules received in each subsequent lot were compared with the previous lot and were matched based on weight, shape and size, colour and external marking, odour, and comparability of contents of opened capsules. Secondly, the trial was carried out at nine hospitals, supporting the generalizability of our results. YXQNG were well tolerated by CCCI patients in this study. The adverse events that occurred in YXQNG-treated patients were similar to those seen in nimodipine-treated patients. In most cases, adverse events were transient, mild to moderate in intensity, and rarely resulted in the need to withdraw study medication.

There were some limitations to this study. First, YXQNG have a complex recipe with a variety of active ingredients, so investigating its pharmacological effects is a great challenge. Secondly, we followed participants for only 8 weeks, so YXQNG's long-term effectiveness remains to be determined. Thirdly, because both drugs showed beneficial effects, and the effects depend on subjective experience or feeling (headache, dizziness, heavy-headed feeling and sleep disorder), it is unclear whether the results are placebo effects, even though the trial was carried out in a double-blind, double-dummy fashion. To avoid this possible pitfall, it is desirable to allocate patients into four groups (i.e. YXQNG (real)/nimodipine (real), YXQNG (real)/nimodipine (placebo), YXQNG (placebo)/nimodipine (real), and YXQNG (placebo)/nimodipine (placebo)) to compare the results.

In conclusion, this large-scale, randomized, double-blind, controlled trial indicates that YXQNG may be a useful treatment in the management of CCCI. Longer-term studies involving larger clinical samples are warranted to assess the generalizability of our findings and to deepen our understanding of this promising therapeutic approach.


This study was funded by Tianjin Tianshili Pharmaceutical Co., Ltd, the Scientific Research Fund of Fujian Provincial Department of Health (No. WZY0622; No. 2011-CX-29), Fujian Department of Health Fund (No. JA11141), Chen Keji Integrative Medicine Development Foundation (No. CKJ2008002, CKJ2007036), the Open Fund of Fujian Key Laboratory of Integrative Medicine on Geriatrics (No. 2008J1004-15ckj2008052) and Fujian Department of Education Fund (zlcxn03). The authors would like to acknowledge the commitment and hard work of additional members of the Study Group: Anhui Provincial Hospital (Hefei, China), the First Affiliated Hospital of Anhui Medical University (Hefei, China), Xiamen First Hospital Affiliated to Fujian Medical University (Xiamen, China), Jiangshu Provincial Hospital (Nanjing, China), Jiangxi Provincial Hospital (Nanchang, China), First Hospital Affiliated to Zhejiang Medical University (Hangzhou, China), and Qilu Hospital Affiliated to Shandong Medical University (Jinan, China).