Chronic heart failure (CHF) is the leading cause of hospitalization in the aged population worldwide and negatively affects the quality of life of patients [
Based on the theory of Traditional Chinese Medicine (TCM), the major cause of heart failure is heart Yang deficiency that results from Qi inadequacy and blood stasis. Some traditional Chinese herbs have demonstrated safety and efficacy for the management of heart failure in either animal models or humans. For example, velvet antler of deer ameliorated cardiac dysfunction associated with heart failure in a rat myocardial model with heart failure following myocardial infarction [
Shenfu injection (SFI) is a specific TCM extracted from two types of herbs, ginseng radix et rhizome, and radix aconiti carmichaeli. SFI has been shown to exhibit a variety of pharmacological activities, including elevating blood pressure and potentiating myocardial contractility, and has been used for many years to treat patients with cardiovascular diseases in China, such as dilated cardiomyopathy [
This study was a randomized, double-blinded, multicenter, placebo-controlled trial. A total of 160 patients at 11 clinical research centers in China were registered for this study (Supplemental Table
The inclusion criteria were as follows: (1) according to the diagnostic criteria defined for coronary heart disease, patients had occluded myocardial infarction with a stricture rate of the coronary artery main branch (at least 1 branch) of more than 50%, regardless of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) therapy; (2) according to the diagnostic criteria of CHF during acute aggravation, patients had a left ventricular ejection fraction (LVEF) ≤50% as determined by the improved Simpson method [
The exclusion criteria were as follows: (1) acute coronary syndrome, acute myocardial infarction within 6 months, revascularization or intention to undergo revascularization within 6 months, cardiogenic shock, serious arrhythmias, cardiomyopathy, rheumatic valvular heart disease, myocarditis, constrictive pericarditis, and pulmonary embolism within a week; (2) severe liver and renal insufficiency (glutamic oxalacetic transaminase [ALT] ≥3 times normal upper limit, creatinine [Cr] ≥3 mg/dL); (3) severe primary disease in the endocrine and hematopoietic system; (4) intention to become pregnant or breastfeed; (5) psychopath; (6) allergy to SFI; (7) participation in other trial within the previous 3 months; (8) life expectancy <3 months as judged by the investigator; and (9) failure to fulfill or obey the study guidelines as judged by the investigator.
After application of the inclusion and exclusion criteria, a total of 160 patients were finally enrolled in our study and randomly assigned to two groups: the placebo group, in which 80 patients were given the placebo (GS 150 ml), and the SFI group, in which 80 patients were treated with SFI (SFI 50 ml + GS 100 ml). Patients in both groups simultaneously received their usual care and medications such as diuretics, angiotensin converting enzyme inhibitors (ACEIs), or angiotensin II receptor blockers (ARBs),
The primary endpoints were NYHA classification and TCM syndrome scores. The secondary endpoints included Lee’s CHF scores, 6-minute walk distance (6MWD), LVEF, and the incidence rate of cardiovascular events and heart failure emergency/rehospitalization. The safety endpoints included tests of blood, urine, stool, the levels of serum K, Na, Cl, ALT, aspartate aminotransferase (AST), blood urea nitrogen (BUN), and Cr, and the occurrence of adverse events (AEs)/adverse drug reactions (ADRs).
The efficiency standard was formulated in reference to “the principle of clinical research on treating heart failure with new Chinese Medicine [
Excellent: heart failure was essentially ameliorated or the NYHA classification increased by at least 2 levels. Valid: NYHA classification increased by 1 level. Invalid: NYHA classification remained the same before and after the treatment. Worsened: NYHA classification decreased by at least 1 level.
Excellent: Clinical symptoms were markedly improved, and the TCM syndrome score decreased by 70% compared with that before treatment. Valid: Clinical symptoms were improved, 30% ≤ TCM syndrome score < 70%. Invalid: Clinical symptoms were not improved. Worsened: Clinical symptoms were worsened. The TCM syndrome score increased.
Excellent: Scores decreased by 75% compared with that before treatment. Valid: 50% ≤ decreased scores < 75%. Invalid: 0 ≤ decreased scores < 50%. Worsened: Decreased scores < 0.
All statistical analyses were performed at an independent institute—Tianjin Institute of Traditional Chinese Medicine Engineering—with SAS software, version 9.1.3. Data were analyzed according to the full analysis set principle. Continuous variables are presented as the mean ± standard deviation (SD). The comparability of the characteristics between the two study groups was assessed using a two-sample Student t-test for continuous variables and the chi-square test or Wilcoxon test, when appropriate, for categorical variables. The Wilcoxon paired signed-rank test was used for within-group comparisons. The statistical difference in the AE incidence rate between the two study groups was assessed using
From April 18, 2013, to August 2, 2015, a total of 160 patients were enrolled in this study and randomly assigned to the placebo and SFI groups at a 1:1 ratio. Among these participants, 154 were followed up for 28 ± 3 days after the treatment (76 in the SFI group and 78 in the placebo group); 144 were enrolled in the full analysis set (FAS) (74 in the SFI group and 70 in the placebo group); and 137 were enrolled in the per-protocol set (PPS) (71 in the SFI group and 66 in the placebo group). Medication compliance of all patients was recorded (102.32% in the SFI group and 101.22% in placebo group; Figure
Flow chart of patient selection and study design.
The recorded demographic and clinical characteristics included age, gender, medical history, course of heart failure in the acute aggravation phase, information of background medication, NYHA classification, TCM syndrome score, Lee’s heart failure score, 6MWD, and LVEF. The distributions of the demographic and clinical characteristics between the SFI and placebo groups were well balanced and homogeneous (P
Comparison of demographic and baseline clinical characteristics of participants between the SFI and placebo groups.
Characteristic | SFI | Placebo | Statistics | P value |
---|---|---|---|---|
| ||||
Age ( | 68.58±8.42 | 68.14±8.73 | -0.3042 | 0.7610 |
Gender | ||||
Male n(%) | 42(56.76%) | 48(68.57%) | 2.1424 | 0.1433 |
Female n(%) | 32(43.24%) | 22(31.43%) | ||
Weight ( | 65.43±13.10 | 66.26±11.82 | 0.5744 | 0.5657 |
Height ( | 164.10±7.30 | 166.00±6.60 | 1.63 | 0.1052 |
SBP ( | 132.55±21.89 | 133.27±19.47 | 0.2648 | 0.7912 |
DBP ( | 77.26±10.77 | 77.64±11.04 | 0.3134 | 0.7540 |
Heart rate ( | 86.5±21.6★ | 76.1±20.0 | -3.1526 | 0.0016 |
| ||||
Disease course of CHF ( | 4.62±6.07 | 3.76±3.69 | -0.4280 | 0.6687 |
Disease course of acute exacerbation ( | 6.08±5.07 | 6.94±8.27 | 0.1853 | 0.8530 |
History of myocardial infarction n(%) | 38(52.05%) | 43(61.43%) | 1.2785 | 0.2582 |
History of arrhythmia n(%) | 20(27.03%) | 19(27.14%) | 0.0002 | 0.9875 |
History of hypertension n(%) | 51(70.83%) | 44(62.86%) | 1.0197 | 0.3126 |
History of diabetes n(%) | 26(35.14%) | 16(22.86%) | 2.6248 | 0.1052 |
| ||||
Antiplatelet n(%) | 63 (85.14%) | 61 (87.14%) | 0.1212 | 0.7277 |
Beta-blockers n(%) | 36 (48.65%) | 44 (62.86%) | 2.9412 | 0.0863 |
ACE inhibitors n(%) | 32 (43.24%) | 35 (50.00%) | 0.6601 | 0.4165 |
ARB inhibitors n(%) | 23 (31.08%) | 19 (27.14%) | 0.2700 | 0.6033 |
Statins n(%) | 57 (77.03%) | 50 (71.43%) | 0.5905 | 0.4422 |
Nitric acid lipid n(%) | 44 (59.46%) | 44 (62.86%) | 0.1747 | 0.6759 |
Ca-antagonist n(%) | 18 (24.32%) | 17 (24.29%) | 0.0000 | 0.9957 |
Aldosterone receptor antagonist n(%) | 50 (67.57%) | 43 (61.43%) | 0.5927 | 0.4414 |
Diuretics n(%) | 45 (60.81%) | 35 (50.00%) | 1.7027 | 0.1919 |
Digoxin n(%) | 29 (39.19%) | 24 (34.29%) | 0.3719 | 0.5420 |
| ||||
TCM syndrome score ( | 24.54±7.90 | 23.37±7.13 | -1.1902 | 0.2340 |
Lee’s heart failure ( | 6.36±3.25 | 5.71±2.92 | -1.1787 | 0.2385 |
6MWD ( | 163.28±153.48 | 185.70±143.30 | 1.0504 | 0.2935 |
LVEF ( | 38.69±8.52 | 39.82±8.04 | 0.7183 | 0.4726 |
NYHA classification | ||||
III n(%) | 46(62.16%) | 51(72.86%) | 1.8715 | 0.1713 |
IV n(%) | 28(37.84%) | 19(27.14%) |
★P<0.01 compared to control group
SFI treatment significantly improved the NYHA classification by 78.38% compared to the 61.43% increase observed in the placebo group (P=0.0026, relative risk [RR] = 1.2759, 95% confidence interval [CI]: 1.0231–1.5913; Table
Comparison of NYHA classification between SFI and placebo group.
Excellent | Valid | Invalid | Worsened | Effective rate | Statistics | P value | |
---|---|---|---|---|---|---|---|
SFI (n=74) | 18 | 40 | 16 | 0 | 78.38% | 4.9344 | 0.026 |
Placebo (n=70) | 8 | 35 | 27 | 0 | 61.43% |
Effective rate was defined as proportion of all patients who experienced an excellent or valid outcome. Similarly, the ineffective rate was defined as the proportion of all patients who experienced an invalid and worsened outcome.
Comparison of improvement in TCM syndrome score between SFI and placebo groups.
Excellent | Valid | Invalid | Worsened | Effective rate | Statistics | P value | |
---|---|---|---|---|---|---|---|
SFI (n=74) | 22 | 44 | 7 | 1 | 89.19% | 16.3459 | <0.001 |
Control (n=70) | 14 | 28 | 28 | 0 | 60.00% |
Effective rate was defined as proportion of all patients who experienced an excellent or valid outcome. Similarly, the ineffective rate was defined as the proportion of all patients who experienced an invalid and worsened outcome.
SFI treatment had a significantly higher effective rate (70.27%) for improving Lee’s heart failure score compared with placebo treatment (52.17%; P=0.0262, RR=1.3468, 95%CI: 1.0280–1.7646; Table
Comparison of Lee’s heart failure score between SFI and placebo groups.
Excellent | Valid | Invalid | Worsened | Effective rate | Statistics | P value | |
---|---|---|---|---|---|---|---|
SFI (n=74) | 23 | 29 | 21 | 1 | 70.27% | 4.9403 | 0.0262 |
Placebo (n=69) | 15 | 21 | 33 | 0 | 52.17% |
Effective rate was defined as proportion of all patients who experienced an excellent or valid outcome. Similarly, the ineffective rate was defined as the proportion of all patients who experienced an invalid and worsened outcome.
Comparison of change in 6MWD (pre-to-post treatment) between SFI and placebo groups.
Endpoint | SFI (n=70) | Placebo (n=69) | P value | |
---|---|---|---|---|
6MWD | Posttreatment–pretreatment | 113.00±117.55 | 82.99±127.99 | 0.0281 |
Comparison of change in LVEF (pre-to-post treatment) between SFI and placebo groups.
Endpoint | SFI (n=72) | Placebo (n=67) | P value | |
---|---|---|---|---|
LVEF | Post-treatment – pre-treatment | 6.58±9.11 | 4.53±8.21 | 0.2347 |
Comparison of CCEs between SFI and placebo groups.
Endpoint | SFI (n=74) | Placebo (n=70) |
---|---|---|
CCE | 0 (0.00%) | 2 (2.86%) |
revascularization | 0 (0.00%) | 2 (2.86%) |
Death incident | 0 (0.00%) | 1 (1.43%) |
No statistical differences in the occurrence of AEs were observed between the SFI and placebo groups (Table
Comparison of AEs (top 10) between SFI and placebo groups.
ADE | SFI (n=78) | Placebo (n=79) | All (n=157) |
---|---|---|---|
Renal dysfunction | 6 (7.69%) | 4 (5.06%) | 10 (6.37%) |
Liver dysfunction | 1 (1.28%) | 2 (2.53%) | 3 (1.91%) |
Urinary system infection | 5 (6.41%) | 3 (3.80%) | 8 (5.10%) |
Urine protein | 1 (1.28%) | 1 (1.27%) | 2 (1.27%) |
Pulmonary infection | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Anemia | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Hypoglycemia | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Chills | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Erythra | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Diarrhea | 0 (0.00%) | 1 (1.27%) | 1 (0.64%) |
Ureteral calculi cut into stone | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Comparison of ADRs (top 10) between SFI and placebo groups
ADR | SFI (n=78) | Placebo (n=79) | All (n=157) |
---|---|---|---|
Chills | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Erythra | 1 (1.28%) | 0 (0.00%) | 1 (0.64%) |
Total | 2 (2.56%) | 0 (0.00%) | 2 (1.27%) |
Accessory: list of ADRs
Subject number | Group | ADR symptom | ADR description |
---|---|---|---|
006002 | SFI | Chill | Chill occurred after injection of 10 ml SFI. |
010070 | SFI | Erythra | The subject felt itchy skin after 1 day of medication. Skin flushing was seen on the upper parts of the chest and abdomen, the medial buttocks, and both lower limbs. There was scratch, but no break. |
Comparison of incidence of abnormal laboratory indexes between SFI and placebo groups.
Laboratory index | SFI (n=78) | Placebo (n=79) |
---|---|---|
| ||
White blood cell count | 12 (16.00%) | 9 (11.84%) |
Red blood cell count | 10 (13.33%) | 9 (11.84%) |
Hemoglobin | 15 (20.00%) | 12 (15.79%) |
Blood platelet count | 11 (14.67%) | 8 (10.53%) |
| ||
Urine protein | 6 (11.11%) | 10 (16.13%) |
Urine sugar | 4 (7.41%) | 3 (4.84%) |
Urine erythrocyte | 8 (14.81%) | 10 (16.13%) |
Urine white blood cell count | 11 (20.37%) | 8 (12.90%) |
| ||
Red blood cell | 0 (0.00%) | 0 (0.00%) |
White blood cell | 2 (7.14%) | 0 (0.00%) |
Occult blood | 6 (21.43%) | 2 (5.13%) |
| ||
Alanine transaminase (ALT) | 6 (8.45%) | 6 (8.57%) |
Glutamic oxalacetic transaminase (AST) | 7 (9.59%) | 5 (6.76%) |
Total bilirubin | 2 (2.90%) | 5 (7.35%) |
Urea nitrogen | 17 (22.97%) | 13 (17.33%) |
Creatinine | 16 (21.33%) | 20 (26.67%) |
| ||
K | 5 (6.58%) | 2 (2.60%) |
Na | 5 (6.58%) | 6 (7.79%) |
Cl | 3 (3.95%) | 5 (6.49%) |
SFI, as a form of TCM, has been long used in clinical practice in China to treat CHF and has achieved favorable outcomes. However, to the best of our knowledge, this study was the first standard clinical trial, i.e., randomized, multicenter, double-blinded, placebo-controlled trial, to explore the safety and efficacy of SFI for treatment of patients in the acute phase of CHF who were simultaneously receiving standard treatments. The major findings included the following: (1) SFI significantly improved the clinical symptoms of these patients; (2) SFI significantly improved cardiac tolerance; and (3) SFI did not induce AEs or ADRs.
With the acceleration of the aging population and advancement in the treatment of human diseases including cardiovascular disorders, the human life expectancy has been extended. However, the number of patients with CHF has also been increasing. Patients with CHF are often hospitalized with acute symptom exacerbation due to various causes. Such patients mainly present with deterioration of cardiac function accompanied by a decline in athletic tolerance. The quest for treatments to alleviate symptoms of CHF during the acute phase of symptom exacerbation has been an active area of research in the clinic. TCM has been used clinically to treat CHF patients with acute symptom exacerbation in China for a long time [
NYHA, as a simple, accurate index for evaluating heart function, can reflect the severity of acute heart failure, which has been shown to be closely related to survival [
In the present study, we also evaluated the safety of SFI and found no significant differences in the occurrence of ADRs and AEs between the SFI and placebo group, suggesting the appreciable safety of SFI in clinical use.
In the present study, we demonstrated that SFI treatment in combination with conventional therapy for CHF in the acute phase ameliorated cardiac dysfunction and clinical symptoms, increased the 6MWD, and improved patients’ quality of life compared with the conventional therapy alone. We also demonstrated the safety of SFI in clinical use. Future studies with a large cohort are needed to further corroborate our findings and conclusions.
This study was conducted only in some areas, and the observation period was short. Also, we did not see the statistical differences in some endpoint indicators such as CCEs or deaths between these groups. In the future, the study of endpoint events can be carried out sufficiently with greater research funds and manpower.
Shenfu injection
Chronic heart failure
Traditional Chinese Medicine
Adverse event
Adverse drug reaction
New York Heart Association
Coronary artery bypass grafting
Percutaneous coronary intervention
6-min walking distance
Aspartate aminotransferase
Blood urea nitrogen
Full analysis set
Per-protocol set
Glucose.
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
The authors declare that they have no conflicts of interest
Jingyuan Mao conceived and designed the experiments. Xianliang Wang, Zhiqiang Zhao, Tinghai Du, Yuanping Chen, Hao Xu, Nan Liu, Xiaolong Wang, Jianguang Wu, Rong Li, Yong Xu, Yingqiang Zhao, Lei Wang, Jingsong He, Guoyuan Zhao, Yazhu Hou, and Shuai Wang performed the experiments. Junhua Zhang and Chunxiang Liu randomized and managed the data. Jingbo Zhai analyzed the data. Xianliang Wang and Zhiqiang Zhao wrote the paper. Xianliang Wang and Zhiqiang Zhao contributed equally.
(1) Tianjin science and technology project: clinical medicine research center of Internal medicine of TCM in Tianjin (15ZXLCSY00020) and (2) “Innovation team development plan” of Ministry of Education-Research on the prevention and treatment of cardiovascular diseases in traditional Chinese medicine (IRT_16R54) are acknowledged.
Supplemental Table 1: List of participating institutions. Supplemental Table 2: CONSORT 2010 checklist of information to include when reporting a randomised trial. Supplemental Figure 1: Trial flow chart.