Journal of Ethnopharmacology 186 (2016) 136142

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep

A randomized, double-blind, multicenter, placebo-controlled clinical

study on the efcacy and safety of Shenmai injection in patients with
chronic heart failure
Shaoxiang Xian a,n,1, Zhongqi Yang a,1, Jun Lee b, Zhiping Jiang c, Xiaohan Ye d, Luyi Luo e,
Lili Jin f, Tianlun Yang g, Suilin Ye h, Dongfeng Lu i
a

The First Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
The First Afliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Yuebei People's Hospital, Shaoguan, China
d
Dongguan Hospital of Traditional Chinese Medicine, Dongguan, China
e
Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, China
f
Guangdong second Traditional Chinese Medicine Hospital, Guangzhou, China
g
Xiangya Hospital, Central South University, Changsha, China
h
Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou, China
i
The First Afliated Hospital of Guangzhou Medical University, Guangzhou, China
b
c

art ic l e i nf o

a b s t r a c t

Article history:
Received 19 November 2015
Received in revised form
4 February 2016
Accepted 31 March 2016
Available online 1 April 2016

Ethnopharmacological relevance: Shenmai injection (SMI) is a traditional Chinese herbal medicine extracted from Panax ginseng (Panax ginseng C.A. Mey, steamed and dry) and Ophiopogon japonicus
(Ophiopogon japonicus (L.f.) Ker-Gawl, root). It has been widely used for the treatment of chronic heart
failure (CHF) in China. However, the evidence supporting its effects remains unclear due to lack of high
quality trials. The aim of this study was to investigate the efcacy and safety of SMI in CHF patients with
coronary artery disease (CAD).
Materials and methods: This double-blind, multicenter study randomized 240 eligible patients equally to
receive SMI or placebo (100 ml/day) in addition to standard medicines for the treatment of CHF. The
primary endpoint was the New York Heart Association (NYHA) functional classication. The secondary
endpoints were 6-min walking distance (6MWD), short-form 36 (SF-36) hearth survey score, traditional
Chinese medicines (TCM) syndrome score, left ventricular ejection fractions (LVEF) and B-type natriuretic
peptide (BNP) level.
Results: During treatment of 1 week, the NYHA functional classication was gradually improved in both
groups, but the SMI group demonstrated a signicantly greater improvement compared with the placebo
group (p 0.001). Moreover, the improvement in patients received SMI was superior to those in control
group with respect to 6MWD, SF-36 score and TCM syndrome score. Treatment with SMI within 1 week
was well tolerated with no apparent safety concerns.
Conclusions: The integrative treatment with standard medicines plus SMI can further improve NYHA
functional classication for patients with CHF and CAD. Therefore, SMI could be recommended in the
combination therapy for CHF accompanied with CAD.
& 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Heart failure
Shenmai injection
Randomized controlled trial
Traditional Chinese medicines
Panax ginseng
Ophiopogon japonicas

1. Introduction
n
Correspondence to: The First Afliated Hospital of Guangzhou University of
Chinese Medicine, No. 16 Airport Road, Guangzhou 510000, China.
E-mail addresses: zhongfyy@126.com (S. Xian), zqyang66@163.com (Z. Yang),
junlee008@126.com (J. Lee), jzp7448@163.com (Z. Jiang),
xiaohanye666@126.com (X. Ye), luoluyi8@126.com (L. Luo),
wondergirl2@yeah.net (L. Jin), yangtl44@yeah.net (T. Yang),
suilinye52@163.com (S. Ye), ludf123@126.com (D. Lu).
1
Dr. Shaoxiang Xian and Dr. Zhongqi Yang are the co-rst authors and contributed equally to this work.

http://dx.doi.org/10.1016/j.jep.2016.03.066
0378-8741/& 2016 Elsevier Ireland Ltd. All rights reserved.

Chronic heart failure (CHF) is a major public health problem

and has been singled out as an epidemic (Roger et al., 2004), associated with signicant mortality and heavy healthcare expenditures (Go et al., 2014; Roger, 2013). Evidence from epidemiology conrmed that coronary artery disease (CAD) have the
largest population attributable risk for HF (Owan et al., 2006;
Roger, 2013) and is correlated with poor prognosis for patients
with CHF (Murdoch et al., 1998). Treatment strategies have been

S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

developed based upon the understanding of the pathophysiological mechanisms in HF (Kemp and Conte, 2012). According to the
latest guidelines for HF (McMurray et al., 2012; Yancy et al., 2013),
standard medicines include diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, aldosterone antagonist and digitalis. Despite advances in the drug
and surgical treatment, the survival estimates remain 50% and 10%
at 5 and 10 years, and rates of readmissions continue to rise (Roger, 2013). Therefore, improved treatments are imperative.
In the theory of traditional Chinese medicine (TCM), Qi usually
refers to life energy that manifests simultaneously on the physical
and mental-spiritual level (Maciocia, 2005). Yin and Yang are
terms used to describe relative opposite qualities or manifestations of Qi. From the perspective of TCM, the principal problems of
CHF are deciency of Qi and inadequacy of either Yin or Yang,
which impair the circulation of blood (Li et al., 2013b; Mao et al.,
2009; Tang and Huang, 2013), leading to retention of body uid
and stasis of blood. Shenmai injection (SMI) is a traditional Chinese herbal medicine extracted from Panax ginseng (Panax ginseng
C. A. Mey, steamed and dry) and Ophiopogon japonicus (Ophiopogon japonicus (L.f.) Ker-Gawl, root), with effects of tonifying Qi,
nourishing Yin and replenishing bodily uids (Chen et al., 2012;
Ma et al., 2010; Yu et al., 2014). Therefore, SMI has long been used
as a complement to the standardized treatments for CHF in China.
Although its efcacy against heart failure has been demonstrated
in several studies, the poor quality of these trials compromised the
reliability of the evidence (Chen et al., 2012). This clinical trial was
aimed to further evaluate whether CHF patients with CAD can
benet from the integrative treatments with standard medicines
plus SMI.

137

comorbidities, only the medicine that fullled the corresponding

guidelines was enabled.
2.2. Study products
SMI, prepared from Panax ginseng and Ophiopogon japonicus,
has been mass-produced as a patented drug based on the national
standards approved by CFDA (China Food and Drug Administration). Briey, Panax ginseng (100 g) and dried tuber roots of
Ophiopogon japonicus (100 g) were respectively extracted by reuxing with 90% ethanol for 2 h each time (Panax ginseng, six
times; Ophiopogon japonicus, two times). The extract was condensed to the concentration of 0.30.4 g crude drug weight/ml
solution. The solution was then stirred with 1% acticarbon for 1 h,
followed by ltration and dilution with water for injection. This
process was repeated twice. Finally, polysorbate 80 was added and
the solution was diluted to 1000 ml with water for injection. SMI
(batch number: 1105079) used in our research was manufactured
in accordance with applicable GMP by Qingchunbao Pharmaceutical Co., Ltd (Hangzhou, China). The batch sample analyses and
characteristic records of SMI were maintained. As reported previously (Wu et al., 2013), high-performance liquid chromatography
(HPLC) analysis was performed to identify the phytochemical
characteristics of SMI. The HPLC chromatogram of SMI including
ginsenosides as standard was showed in Fig. 1. The components
conformed to the national standards of Shenmai injection approved by CFDA.
The placebo (5% glucose injection) was proprietary preparations produced by Dongguan Lifeline Pharmaceutical Co., Ltd with
the batch number of 11070603. In order to avoid the exposure of
study drugs from the brown color of SMI, light-resistant containers
and infusion apparatus were used during treatment.

2. Material and methods

2.3. Study participants
2.1. Study design
This study was designed as a multicenter, randomized, doubleblind, placebo-controlled study based on standard therapy and
parallel groups. The trial was conducted in eight A-level hospitals
and enrolled 240 patients with CHF and CAD based on the inclusion and exclusion criteria. The study conforms to the Declaration
of Helsinki and was performed in accordance with the Good Clinical Practice and national regulations. The trial protocol and its
informed consent form were approved by appropriate independent ethics committees. All participants submitted informed
consent before the start of the study. The clinical trial has been
registered at Chinese Clinical Trial Registry with the registration
number: ChiCTR-TRC-12003063.
Block randomization with stratication was used to assign
eligible patients to either SMI group or placebo group in the ratio
of 1:1. The corresponding randomization code was generated by
SAS software (SAS Institute, Cary, North Carolina) according to the
number of enrolled patients in each center and was held centrally
by the rst afliated hospital of Guangzhou University of Chinese
Medicine. All patients and investigators were kept unaware of the
treatment allocation.
Prior to this trial, patients had received standard medicines for
at least 1 month with reference to the Chinese Society of Cardiology guidelines for the treatment and diagnosis of CHF. Besides
standard medicines, eligible patients were randomized to receive
100 ml/day SMI or 100 ml/day 5% glucose injection (placebo) intravenously at the rate of 2040 drops per minute, for consecutive
7 days. The baseline of patients was tested before intervention.
After treatment for 4 and 7 days, patients were evaluated for the
effects from the intervention. Except for SMI, any other TCM that
could confuse the outcome of SMI was forbidden. In the case of

Inclusion criteria include male and female patients with 4080

years of age; history of CHF combined with CAD; New York Heart
Association (NYHA) functional classication ; diagnosis of QiYin deciency (Wang et al., 2013); subjects received standard
medicines for at least 1 month, whose condition remained unstable and required further treatment in hospital; submission of
informed consent. Exclusion criteria include the patients with
acute cardiac dysfunction; exacerbation of CHF induced by the
adverse effects of digitalis; comorbidities of cardiac shock, malignant cardiac arrhythmia, degree type or severer atrioventricular block, obstructive myocardiopathy, unrepaired valvular
heart disease, constrictive pericarditis, cardiac tamponade, pulmonary embolism, acute myocardial infarction, or uncontrolled

Fig.1. The HPLC chromatogram of SMI (Shenmai injection). (A) The HPLC chromatogram of control solution that contains six main compounds of SMI (ginsenoside Rg1, Re, Rf, Rb1, Rb2 and Rd); (B) The HPLC chromatogram of SMI. In both
(A) and (B), chromatographic peaks from 1 to 6 represented Rg1, Re, Rf, Rb1, Rb2
and Rd respectively.

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S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

infection; subjects with serious liver, kidney, or hematopoietic

system disease; alanine transaminase or aspartate transaminase
levels480 U/L; mental disorder; diabetes patients with uncontrolled
plasma
glucose
level
(fasting
plasma
glucose 4 7.0 mmol/L, postprandial plasma glucose 410.0 mmol/
L); pregnancy or breastfeeding; participation in other clinic trials
within 1 month; allergic to SMI.

3. Results
3.1. Patient characteristics

The primary endpoint was NYHA functional classication. The

secondary endpoints were 6-min walking distance (6MWD),
short-form 36 (SF-36) hearth survey score, TCM syndrome score
(see detailed evaluation method in Appendix A), left ventricular
ejection fractions (LVEF) and B-type natriuretic peptide (BNP) level. All these endpoints were tested at baseline. NYHA functional
classication, TCM syndrome score and BNP level were evaluated
following intervention for 4 and 7 days. 6MWD, SF-36 hearth
survey score and LVEF were performed after treatment for 7 days.

Patient enrolment was started in September 2011 and completed in August 2012. According to the inclusion and exclusion
criteria, 240 patients (SMI, n 120; placebo, n 120) were enrolled
and randomized from eight A-level hospitals in China. Patient
disposition is summarized in Fig. 2. Overall, 240 patients received
study drug were included in the safety evaluation. Among them,
228 patients (SMI, n 114; placebo, n 114) were eligible for the
primary analysis. Three patients (SMI, n 2; placebo, n 1) were
excluded from the primary analysis due to the violation of the
inclusion criteria. The other eight patients (SMI, n4; placebo,
n4) were excluded because of protocol deviations that could
affect efcacy assessments, the most common being use of other
TCMs during the treatment period (SMI, n 4; placebo, n 2). One
placebo recipient withdrew the informed consent form. The distribution of the demographic and baseline characteristics between
SMI and placebo groups were well balanced (Table 1).

2.5. Laboratory tests and Safety monitoring

3.2. NYHA functional classication

2.4. Clinical endpoints

Routine examinations (blood and urine routine examination,

feces examination, blood biochemistry, liver and renal function,
and electrocardiogram) were carried out at baseline and after
treatment for 7 days. Safety was evaluated by vital signals (temperature, blood pressure and heart rate), laboratory tests, and
adverse events (AEs) that were monitored throughout the study.

2.6. Statistical analysis

The sample size was estimated based on the expected improvement in the primary endpoint (NYHA functional classication) of SMI through the previous clinic trials, from which the
mean percentage of patients with improve NYHA function was
85.81% and 63.22% in SMI and placebo groups, respectively.
Therefore, assuming an additional 23% improvement in NYHA
function following treatment with SMI (SMI, 86%; placebo, 63%)
and given a power (1-) of 80% and two-tail typeerror of 5%, 68
patients would be required for each group to detect the superiority
of SMI as compared with placebo (superiority margin 0.05).
Moreover, considering the requirements of the drug registration
regulation of CFDA and the dropout rate was approximately 20%, a
total of 240 patients (120 per treatment group) was needed to be
randomized to achieve the required number of patients for the
efcacy analysis.
Statistical analyses were performed using SAS. The analysis for
the primary endpoint was based on the full analysis set (FAS).
Continuous variables were presented as mean 7SD, except for
BNP level, which is natural logarithm-transformed before analysis.
Generally, continuous variables were assessed by Student's t-test
between groups or by paired t-test within group, while discrete
variables were analyzed by chi-square test. For the comparison of
NYHA functional classication between groups, the Cochran
Mantel Haenszel (CMH) test was performed. The Fisher exact test
was used to analysis the ratio of adverse events between groups.
For NYHA functional classication and TCM syndrome score, the
missing data was estimated by the last observed carried forward
(LOCF) with at least one post-treatment evaluation (Shao and
Zhong, 2003). Signicance was attributed when a two-tail
p o0.05.

At enrolment, the majority of patients were in NYHA to

(89.5%) and the remaining patients were in NYHA (10.5%).
Baseline NYHA functional classication was similar between the
two groups (Table 1). After treatment with either SMI or placebo
plus standard medicines, the frequency of NYHA to patients
gradually increased, whereas the frequency of NYHA to patients decreased continuously (Fig. 3). The frequency of NYHA and
NYHA within SMI group from baseline over 7 days presented an
increase of 22.8% and 12.3%, as opposed to 8.8% and 14.9% in
placebo group, while the frequency of NYHA and NYHA decreased by 28.1% and 7.0% in SMI group, in contrast to 19.3% and
4.4% in placebo group. SMI treatment resulted in superior improvements of NYHA functional classication compared with the
placebo (p 0.001, Fig. 3).
3.3. 6-min walking distance
As shown in Fig. 4, the two groups demonstrated similar
6MWD at baseline (p 0.418). After treatment for 7 days, 6MWD
was signicantly improved within both groups (SMI, p o0.001;
placebo, p o0.001). On day 7, patients in the SMI group had a
mean 6MWD change from baseline of 112.21 m, whereas patients
in placebo group had a mean change of 63.03 m. Compared with
placebo, treatment with SMI resulted in a statistically signicant
treatment difference in the mean 6MWD change (p o0.001, Fig. 4).

Fig. 2. Flow chart of patients throughout the study. (FAS, Full Analysis Set).

S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

139

Table 1
Baseline characteristics of patients enrolled in the study.
Characteristics

Placebo (n 114)

Shenmai injection
(n 114)

Sex
Men
Women
Age

66 (57.9%)
48 (42.1%)
68.127 8.88

71 (62.3%)
43 (37.7%)
68.95 79.91

0.51

Measurements
Weight (kg)
Height (cm)
BMI (kg/m2)
Heart rate (beats/min)
Systolic BP (mmHg)
Diastolic BP (mmHg)

61.03 7 11.05
161.85 77.88
23.25 7 3.75
77.46 7 11.28
128.96 720.79
75.727 10.78

62.06 712.50
163.007 8.13
23.25 7 3.44
78.85 7 15.12
128.39 719.43
75.577 12.09

0.51
0.28
1.00
0.43
0.83
0.92

0 (0.0%)
56 (49.1%)
43 (37.7%)
15 (13.2%)
48 (42.1%)
39.25 7 7.59

0 (0.0%)
55 (48.2%)
50 (43.9%)
9 (7.9%)
46 (40.4%)
38.84 7 7.65

0.70
0.80

NYHA class

LVEF ( r50%)
LVEF (%) of Patients
with LVEFr 50%

p-Value

0.50

Fig. 3. The effect of Shenmai injection on the results of CHF NYHA functional
classication.

0.62

Medications
ACE inhibitor
ARB
Beta-blocker
Digoxin
Loop diuretic
Calcium channel
blockers
ADP receptor blocker
Cephalosporins
Statins

101 (88.6%)
33 (29.0%)
70 (61.4%)
36 (31.6%)
44 (38.6%)
32 (28.1%)

93
40
66
34
43
37

(81.6%)
(35.1%)
(57.9%)
(29.8%)
(37.7%)
(32.5%)

0.14
0.32
0.59
0.77
0.89
0.47

58 (50.9%)
7 (6.1%)
74 (64.9%)

51 (44.7%)
12 (10.5%)
64 (56.1%)

0.35
0.23
0.18

Laboratory
measurements
Sodium (mmol/l)
Potassium (mmol/l)
Creatinine (mol/l)
Hemoglobin (g/l)
ALT (U/l)
AST(U/l)
Six-minute walk test
(m)
BNP (pg/ml)a

138.617 13.01
5.32 7 12.98
99.81 7 46.00
124.867 18.55
21.45 7 13.10
24.407 10.86
318.58 7 128.67
(n 113)
4.94 7 1.84 (n 107)

140.067 3.29
4.05 7 0.47
97.217 32.93
128.007 17. 13
22.69 7 15.12
26.58 7 11.34
304.46 7133.60

0.25
0.30
0.63
0.18
0.51
0.14
0.42

5.077 1.80 (n 106)

0.61

Fig. 4. Change in 6-Min Walking Distance (6MWD) from Baseline over 7 days
treatment with Shenmai injection. ***p o 0.001 compared with the Placebo group.

Values are expressed as Mean 7 SD or n (%); BMI, Body Mass Index; BP, Blood
Pressure; NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; ACE, Angiotensin-Converting Enzyme; ARB, Angiotensin- Receptor Blockers;
ADP, Adenosine Diphosphate; ALT, Alanine Transaminase; AST, Aspartate Transaminase; BNP, B-type Natriuretic Peptide.
a

BNP level is natural logarithm-transformed before analysis.

3.4. SF-36 health survey scores

Fig. 5 shows the mean change of SF-36 health survey scores
from baseline over 7 days. On day 7, patients receiving SMI presented higher SF-36 health survey scores compared with patients
with placebo (po 0.001). Compared with baseline, the mean
change within the SMI group was an increase of 13.44 (p o0.001),
and the change in the placebo group was an increase of 5.71
(p o0.001). Moreover, the difference in the mean change of the SF36 health survey scores was also signicant between two groups
(p o0.001).
3.5. TCM syndrome scores
A favorable effect of SMI was also observed on the TCM

Fig. 5. Change in Short-Form 36 (SF-36) Health Survey scores from Baseline over
7 days treatment with Shenmai injection. ***p o 0.001 compared with the Placebo
group.

syndrome scores. After treatment for 4 and 7 days, TCM syndrome

scores decreased signicantly within both SMI and placebo group
(Fig. 6A). The mean change in TCM syndrome score from baseline
over 4 and 7 days was higher in SMI group, compared with placebo group (Fig. 6B).
3.6. LVEF and BNP level
The analysis of LVEF was based on patients with LVEFr 50%
(SMI, n46; placebo, n48; p 0.70). At baseline, the LVEF level
in those patients did not differ between the SMI and placebo

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S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

Fig. 6. TCM syndrome score (A) and Mean Change of TCM syndrome score (B) after treatment with Shenmai injection for 4 and 7days. Mean change of TCM syndrome
score (Baseline-4days) or (Baseline-7days). ***p o 0.001 compared with the baseline of the same group; *p o0.05 compared with the Placebo group.

Table 2
The changes of LVEF and BNP from baseline over 7 days treatment with Shenmai injection.
Item

Time point

Placebo
Outcome

LVEF(%) of Patients with LVEF r 50%

BNP (pg/ml)a

Baseline
7 days
Baseline
4 days
7 days

39.25 7 7.59 (n 48)

42.50 7 10.13 (n 44)
4.94 7 1.84 (n 107)
4.58 7 1.82 (n 97)
4.65 7 1.74 (n 103)

Shenmai injection
Mean changefrom baseline

3.717 9.27 (n 44)

 0.277 0.78 (n 93)
 0.167 0.86 (n 99)

Outcome

Mean changefrom baseline

38.84 7 7.65 (n 46)

40.687 10.28 (n 41)
5.0771.80 (n 106)
4.99 7 1.85 (n 92)
5.02 7 1.73 (n 95)

2.22 7 8.26 (n 41)

 0.05 7 0.94 (n 87)
 0.137 0.84 (n 90)

Values are expressed as Mean 7SD; LVEF, Left Ventricular Ejection Fraction; BNP, B-type Natriuretic Peptide.
a

BNP level is natural logarithm-transformed before analysis.

groups. A trend towards higher LVEF level was observed on day

7 within each groups, however the difference in the mean LVEF
level change was not statistically signicant between SMI and
placebo (Table 2). Baselines of BNP levels were similar in the two
groups. After treatment for 7 days, the mean change of BNP levels
was also not signicantly different between SMI and placebo
groups (Table 2).

Table 3
Summary of adverse events.

3.7. Safety evaluation

The analysis included all patients who received at least one dose of the study
medication; AEs, Adverse Events.

The safety evaluation included all patients who received at

least one dose of the study drug and had at least one post-baseline
safety assessment. Compared with placebo (data not included),
there was no signicant difference on index of kidney and liver
function (Cr, ALT and AST levels) after treatment with SMI for
7 days between two groups (p 40.05). Moreover, no signicant
difference was also found within the group respectively (p4 0.05).
Treatment with SMI within 1 week was well tolerated with no
apparent safety concerns (Table 3 and Appendix B). Seven patients
experienced AEs during the study: four (3.33%) patients in the SMI
group and three (2.50%) patients in the placebo group. The majority of events were of mild-to-moderate severity (See detailed
AEs information in Appendix B). One AE in SMI group was serious
but caused by acute appendicitis. Two AEs in placebo group was
suspected to be related to guideline medicines which possibly
induced chills, fever and high plasma glucose level. A similar
proportion of patients in each treatment group had an AE that led
to discontinuation of study drug (SMI: n1; placebo: n 1). The

Placebo (n 120) Shenmai injection

(n 120)
Adverse events
3 (2.50%)
Serious adverse event 0 (0.00%)
Drugs induced AEs
2 (1.67%)

4 (3.33%)
1 (0.83%)
0 (0.00%)

p-Value

1.000
1.000
0.245

analysis of drug induced AEs, serious AEs and total AEs revealed no
differences between the two groups (Table 3).

4. Discussion
TCMs have been used for thousands of years in China for promoting the homeostatic balance of the body, which was believed
to be effective, safe and natural (Chen et al., 2012; Tang and Huang,
2013). Shenmai, a traditional Chinese medicine, is derived from
the ancient TCM literature medicine origin as a treatment for QiYin deciency that has been recognized corresponding to the
syndromes of CHF combined with CAD by modern medical experts
in China. Similar to other TCMs, the effects of Shenmai are too
obscure to be understand in terms of TCM theory, which drives the
demand to re-evaluation them by contemporary evidence-based
trials. Although most previous studies of SMI have reported

S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

modest improvements of CHF, few were designed and regulated as

rigorously as the clinical trials in contemporary pharmaceuticals
(Chen et al., 2012), with serious problems involving lack of detailed process of randomization, absence of allocation concealment, unclear baseline characteristics, open-label design, and
small scale of subjects. Therefore, a well-designed study was performed to explore the benets from SMI. Besides these validated
measures, a new index system (Mao et al., 2009) that has been
developed to specially quantify the clinical effects from TCMs
based on TCM syndromes, was used in this clinic trial as a complementary endpoint.
SMI is widely used in China for patients hospitalized due to CHF
and approved by China Food and Drug Administration as a patent
drug. In clinical practice, SMI with a dose of 50100 ml per day is
applied as a complement to standard medicines and is often discontinued after the relief of symptoms or disease remission (Chen
et al., 2012), which usually limited the treatment duration to only
1 week. Importantly, although advocated, this approach (SMI dose:
100 ml/day, treatment duration: 1 week) has never been prospectively validated in clinical trials in CHF. Therefore, this study is
tried to evaluate whether patients with CHF and CAD can benet
from this already acceptable treatment in China.
240 patients with CHF combined with CAD were enrolled and
randomized in this study. The distribution of demographic and
baseline characteristics of included patients were homogeneous.
For patients receiving SMI, the improvement of the primary endpoint (the NYHA functional classication) from baseline over
7 days was superior to those in placebo group. This nding paralleled the improvement in 6MWD, SF-36 hearth survey score and
TCM syndrome scores. Subsequent safety evaluation from the vital
signals, laboratory tests, and adverse events did not show signicant difference between SMI and placebo. Together, our data
suggested that standard medicines plus SMI with a dose of 100 ml
per day could further ameliorate the condition of CHF patients
combined with CAD within the treatment duration of 1 week,
when SMI was well tolerated with no apparent safety concerns. It
is of note that despite demonstration of improvements with these
endpoints based on the current scheme, there is no evidence in
this study to support any improvements in long-term outcomes
and safety of SMI. More extensive research should be performed if
a long-term duration is expected.
CHF is a heterogeneous and complex clinical entity with numerous underlying pathophysiological mechanisms (Francis,
2001; Kemp and Conte, 2012). The underlying mechanisms of
Shenmai may be related to its multiple actions targeting at CHF.
Shenmai could improve a series of hemodynamic parameters
(Chen et al., 2002; Zhang et al., 2008), involving enhancement of
coronary ow, augment of myocardial contractility, reduction of
heart rate and down-regulation of blood viscosity. The study by Liu
showed that Shenmai could inhibit secretion of inammatory
factors, such as TNF-, IL-6 and IL-8 (Liu et al., 2013). In addition,
Wang found that Shenmai could prevent cells from oxidative injury through modulating cellular antioxidants. Therefore, the
mechanisms of Shenmai on CHF may be due to its inhibition of
cardiomyocytes apoptosis by balance between pro-inammatory
and anti-inammatory and down-regulation oxygen free radicals.
Furthermore, Shenmai may possibly delay the cardiac remodeling.
Ni found that Shenmai could inhibit myocardial brosis in rat with
diabetic cardiomyopathy (Ni et al., 2011). Zhang investigated the
effect of SMI on heart failure rats and found SMI could reduce the
plasma concentrations of Ang and endothelin (Zhang et al., 2001).
Although the mechanism of Shenmai has been gradually recognized, it's still unclear which ingredient is really effective.
Therefore, further studies on the isolated active components of
SMI are warranted.
Given the characteristics of the study, several limitations are

141

apparent. Because this study was designed based on the widely

used therapy (SMI dose: 100 ml/day, treatment duration: 1 week)
from clinical practice, the duration was limited to 7 days. However,
it's difcult to obtain the re-admission rate and mortality, which
are important and useful outcomes for evaluation. Moreover, similar to other patented TCMs, the effects of SMI may be questionable due to the variability in concentration levels of active
ingredients. Fortunately, SMI is usually mass-produced based on a
standardized formula. And recent study by Li (Li et al., 2013a) has
also proved that a panel of key ingredients of SMI was relatively
consistent within a statistically acceptable range through simultaneously capturing the entire spectrum of ingredients, which
suggests that the effects from SMI are reliable.
In summary, the results of this study suggest that the integrative treatments with guideline medicines plus SMI could
further improve the condition of patients with CHF and CAD with
respect to NYHA functional classication, 6MWD, SF-36 health
survey score and TCM syndrome score. Therefore, SMI with a dose
of 100 ml per day and treatment duration of 1 week could be recommended as a complement to the standard medicines for patients with CHF combined with CAD.

Contributors
Dr. Shaoxiang Xian and Dr. Zhongqi Yang are the co-rst authors and contributed equally to this work. Shaoxiang Xian and
Zhongqi Yang designed the study. Zhiping Jiang, Xiaohan Ye, Luyi
Luo and Lili Jin conducted the patient inclusion, reviewed all cases,
collected patient information and compiled the data les. Tianlun
Yang, Jun Lee and Suilin Ye collected, processed and compiled the
laboratory data. Jun Lee, Suilin Ye and Dongfeng Lu performed the
statistical analyses. Shaoxiang Xian, Zhongqi Yang, Luyi Luo and
Jun Lee drafted the paper. Shaoxiang Xian, Zhongqi Yang, Xiaohan
Ye and Luyi Luo contributed to critical revision for important intellectual content. All authors approved the nal manuscript.

Funding
This work was supported by the Major Project for Major New
Drugs Innovation and Development from the Ministry of Science
and Technology of China (2008ZX09202-006) and Chiatai Qingchunbao Pharmaceutical Co., Ltd (ZYF-Y-2010-056).

Competing interests
Dr. Shaoxiang Xian received research grants from Chiatai
Qingchunbao Pharmaceutical Co., Ltd. All other authors have declared that they have no relationships relevant to the contents of
this paper to disclose.

Acknowledgements
We are grateful for the contributions of our study team, including study coordinators: Mulan Wang, Yanxin Qian, Linjie Xu
(Chiatai Qingchunbao Pharmaceutical Co., Ltd.); statistical analysis: Zhaosi Xu, Shengpeng Zhang (Guangzhou Yushi Medicinal
Technology Co., Ltd.), Yi Shen (School of Public Health, Zhejiang
University, Hangzhou, China). The funders had no role in the design and conduct of the study; collection, management, analysis,
and interpretation of the data; or preparation and review of the
manuscript.

142

S. Xian et al. / Journal of Ethnopharmacology 186 (2016) 136142

Appendix A. Supplementary material

Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.jep.2016.03.066.

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