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BMC Complementary and Alternative Medicine

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Clinical effects of a standardized Chinese herbal remedy, Qili Qiangxin, as an adjuvant treatment in heart failure: systematic review and meta-analysis

  • Jin Sun1,
  • Kang Zhang1,
  • Wen-Jing Xiong1,
  • Guo-Yan Yang1,
  • Yun-Jiao Zhang1,
  • Cong-Cong Wang1,
  • Lily Lai2,
  • Mei Han1,
  • Jun Ren1,
  • George Lewith2 and
  • Jian-Ping Liu1, 3Email author
BMC Complementary and Alternative MedicineBMC series – open, inclusive and trusted201616:201

https://doi.org/10.1186/s12906-016-1174-1

Received: 19 September 2015

Accepted: 29 June 2016

Published: 11 July 2016

Abstract

Background

Qili Qiangxin capsule is a standardized Chinese herbal treatment that is commonly used in China for heart failure (HF) alongside conventional medical care. In 2014, Chinese guidelines for the treatment of chronic HF highlighted Qili Qiangxin capsules as a potentially effective medicine. However, there is at present no high quality review to evaluate the effects and safety of Qili Qiangxin for patients with HF.

Methods

We conducted a systematic review and meta-analysis and followed methods described in our registered protocol [PROSPERO registration: CRD42013006106]. We searched 6 electronic databases to identify randomized clinical trials (RCTs) irrespective of blinding or placebo control of Qili Qiangxin used as an adjuvant treatment for HF.

Results

We included a total of 129 RCTs published between 2005 and 2015, involving 11,547 patients, aged 18 to 98 years. Meta-analysis showed no significant difference between Qili Qiangxin plus conventional treatment and conventional treatment alone for mortality (RR 0.53, 95 % CI 0.27 to 1.07). However, compared with conventional treatment alone, Qili Qiangxin plus conventional treatment demonstrated a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64) and a significant reduction in re-hospitalization rate due to HF (RR 0.49, 95 % CI 0.38 to 0.64). Qili Qiangxin also showed significant improvement in cardiac function measured by the New York Heart Association scale (RR 1.38, 95 % CI 1.29 to 1.48) and quality of life as measured by Minnesota Living with Heart Failure Questionnaire (MD −8.48 scores, 95 % CI −9.56 to −7.39). There were no reports of serious adverse events relating to Qili Qiangxin administration. The majority of included trials were of poor methodological quality.

Conclusions

When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. It appeared to significantly improve quality of life in patients with HF and data from RCTs suggested that Qili Qiangxin is likely safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further research is warranted, ideally involving large, prospective, rigorous trials, in order to confirm these findings.

Keywords

Qili Qiangxin capsuleChinese herbal medicineHeart failureRandomized clinical trialsSystematic reviewMeta-analysis

Background

Heart failure (HF) is a serious and increasingly prevalent worldwide public health problem and has become a major cause of mortality and morbidity [1]. HF is the most common cause of hospitalization in people aged 65 and older [2] and survival rates are reportedly worse than in cancer [3]. According to the European Society of Cardiology (ESC), approximately 26 million people worldwide suffer from HF and which affects 10 % of people over the age of 70, a prevalence which is expected to rise in coming years.

HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood from the heart. Cardinal manifestations include dyspnea and fatigue, which can limit exercise tolerance as well as create fluid retention, and which may lead to pulmonary and peripheral edema [4]. Furthermore, quality of life (QOL) for patients can be adversely impacted owing to sleep-disordered breathing, cognitive dysfunction and neuropsychological disturbances. Conventional medical care for HR typically involves oxygen therapy, diet, diuretics, angiotensin-converting enzyme inhibitors (ACEI) or beta-blockers [5]. Previous research has estimated that the total estimated direct and indirect cost of HF in the US in 2005 was approximately $27.9 billion, with approximately $2.9 billion alone being spent annually on drugs [6]. Despite this significant annual spend, HF continues to be associated with poor prognosis, with absolute mortality rate remaining approximately 50 % within 5 years of initial diagnosis [7]. It is clear that the effectiveness of available care is limited and which warrants further research into optimizing current treatments.

In the recent 2014 Chinese guidelines for treatment of chronic HR, a Chinese herbal remedy, Qili Qiangxin capsules, was mentioned as a potentially effective treatment [8]. Qili Qiangxin capsule is a standardized Chinese herbal treatment that is widely used in China for HF patients and which is frequently administered alongside conventional medical care. It is prepared from 11 Chinese herbs including astragali radix, ginseng radix et rhizoma, aconite lateralis radix preparata, salvia miltiorrbiza radix et rhizoma, semen descurainiae lepidii, alismatis rhizoma, polygonati odorati rhizoma, cinnamomi ramulus, carthami flos, periploca cortex, and citri reticulatae pericarpium. Previous research has suggested that Qili Qiangxin may have a role in the treatment of HF through a number of different mechanisms, for example reducing N-terminal pro-brain natriuretic peptide (NT-proBNP), high levels of which are associated with cardiac ventricular volume and pressure overload [9]. In a study on rats with myocardial infarction (MI), Qili Qiangxin induced heart muscle regeneration and improved cardiac function through regulating the balance between tumor necrosis factor (TNF)-α and interleukin (IL)-10, factors closely associated with inflammatory processes in HF [10]. This suggests promise in this area of research which may be of significant interest to the international medical community and which warrants a robust review of the current evidence to date. A number of systematic reviews have been published in this area. However, all have been published in Chinese and have various shortcomings such as insufficient searches, inappropriate outcome selection and lack of quality assessment, leading us to question the scientific rigor of the results and subsequent recommendations [1116]. The aim of this study was to evaluate the effects and safety of Qili Qiangxin for patients with HF by conducting a systematic review and meta-analysis.

Methods

The method used to conduct this systematic review has been previously published in a registered protocol [PROSPERO registration: CRD42013006106]. This review was constructed using the PRISMA guidelines (Additional file 1).

Search strategy

The following electronic databases were searched from date of inception to March 2015: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue January, 2015), China National Knowledge Infrastructure (CNKI), VIP Database, Sino-Med Database, and Wanfang Database. We used the following search terms: (“Qili Qiangxin” OR “qiliqiangxin” OR “qiangxinli”) and (“heart failure” OR “cardiac failure” OR “heart decompensation”). We searched for trials from mainstream registries including Current Controlled Trials (http://www.controlled-trials.com), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; http://apps.who.int/trialsearch/), ClinicalTrials.gov trials registry (http://www.clinicaltrials.gov), the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au), and Centre Watch (http://www.centerwatch.com). We also hand-searched the reference lists of all full text papers for additional relevant reports. No language restrictions were imposed.

Inclusion criteria

We accepted RCTs regardless of blinding procedures and included only parallel design studies. Only human studies were included in this review and we required the use of internationally-accepted criteria for diagnosis of HF. We placed no other requirements of the participant population in terms of gender, age, etiology, ethnic group, severity or course of disease. Only Qili Qiangxin capsules, composed of the aforementioned 11 Chinese herbs, were accepted as the intervention. This could be used alone or alongside appropriate control treatments such as placebo, conventional treatment or no treatment, and trials with any other Chinese herbal medicine in control group will be excluded. Our primary outcome measures were all-cause mortality or cardiovascular mortality due to HF, major cardiovascular events such as MI, outpatient visits, hospitalizations or re-admission for HF. Secondary outcomes measures were quality of life (QOL) measured by Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association (NYHA) functional classification, echocardiography measurements, six-minutes walking distance (6MWD), plasma amino-terminal pro-brain natriuretic peptide (NT-pro-BNP). We also collected safety and adverse events data. We included only RCTs reporting one or more of these outcomes.

Data extraction and quality assessment

Two authors (from J Sun, K Zhang, WJ Xiong, and YJ Zhang) independently identified articles for eligibility with any disagreements resolved through discussion with a third party (JP Liu). Two authors independently extracted data and which included patient characteristics, details of the intervention and control groups, outcome measures and main results. The same process was used to assess the methodological quality of included RCTs using the risk of bias tool as described in the Cochrane Handbook for Systematic Reviews of Interventions [17]. This process requires seven criteria to be assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, free of selective reporting, and other bias.

Strategy for data synthesis

Statistical analyses were performed by using RevMan 5.2 software (The Cochrane Collaboration). Pooled risk ratio (RR) with 95 % confidence interval (CI) of dichotomous outcomes was used to estimate report effect. Continuous data was presented as mean difference (MD) with 95 % CI. We used a fixed effect model unless there was evidence of heterogeneity. Heterogeneity was assessed using both the Chi-squared test and the I-squared statistic, and we considered an I-squared value greater than 50 % to be indicative of substantial heterogeneity. If missing data from the original trials are available, intention-to-treat analysis will be applied for primary outcome.

Results

Description of studies

Our search in March 2015 from six databases and other sources identified 1,390 potentially eligible articles. After removing duplicates and reviewing full text articles, we eventually included 129 randomized clinical trials published as 131 articles (Fig. 1). All 129 studies were included in our qualitative synthesis and of these, 117 studies were eligible for our meta-analysis.
Fig. 1

Flow chart of study searching and selection

Study characteristics

Included trials were published between 2005 and 2015 with a larger proportion of trials published in 2013 (n = 41 trials, 31.78 %) and 2012 (n = 23 trials, 17.83 %). The 129 trials involved 11,547 patients diagnosed with HF with an age range of 18 to 98 years. Sixteen trials enrolled only elderly patients over the age of 60 (n = 16, 12.40 %). The majority of trials included both male and female patients (n = 127 trials, 98.45 %). Two trials included only male patients (Wei XB 2013, Miao S 2013); two trials provided gender details only for participants who completed the trial (Li XL 2013, Kuang JB 2008). 58.23 % of total populations were male except one trial failed to provide gender detail (Tao X 2011).

Included trials used the following diagnostic criteria: American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European Society of Cardiology (ESC) guidelines, World Health Organization/International Society and Federation of Cardiology (WHO/ISFC) guidelines, World Health Organization/International Society of Hypertension (WHO/ISH) guidelines, Chinese Medical Association (CMA) guidelines, guidelines issued by Ministry of Health (MoH) in China, Framingham criteria, or textbook criteria which were consistent with internationally-used diagnostic criteria .

One hundred seventeen trials (s1-s118, Additional file 2) involving 10,170 patients compared Qili Qiangxin capsules plus conventional treatment to conventional treatment alone. Three trials (s119-s121, Additional file 2) involving 702 patients compared Qili Qiangxin capsule plus conventional treatment to placebo plus conventional treatment. Nine trials (s122-s131, Additional file 2) included 675 patients comparing Qili Qiangxin capsules plus conventional treatment to recommended pharmaceuticals (including thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, hydrochlorothiazide and digoxin plus conventional treatment). Almost all patients in the included trials presented with comorbidities such as hypertension, hypotension, valvular heart disease, pulmonary heart disease, cardiomyopathy, diabetes mellitus, chronic renal insufficiency, coronary heart disease, acute MI and sinus bradycardia. The duration of treatment ranged from 1 to 12 months, and the most commonly adopted was 1 month (n = 54 trials). Nineteen trials had 6 or more months of treatment.

The main outcome in the majority of trials was reported to be left ventricular ejection fraction (LVEF) (n = 91 trials). Other primary outcomes adopted included mortality (n = 6 trials), major cardiovascular events (n = 3 trials) or re-hospitalization (n = 9 trials). Details of each study are listed in Table 1.
Table 1

Characteristics of included studies

ID (Author year)

Disease

Setting (in/out patients)

Diagnosis criteria

Sample size

Age-T

Age-C

Men-%

Course of treatment

Bai LQ 2013

HF

in

NYHA

40

45 ± 3.7

52 ± 4.2

57.5

3M

Cai RF 2013

CHF

NA

CMA 2009; MoH 2002; Framingham criteria; NYHA

50

52-80

52-81

54

4W

Cai YP 2013

CHF

in or out

Framingham criteria; NYHA

108

73.2 ± 11.5

60.19

6M

Chen L 2009

CHF

in

ACC/AHA 1995; MoH 2002; NYHA

61

67.2 ± 11.5

63.1 ± 13.8

57.38

4W

Chen TC 2013

CHF

NA

CMA 2007; NYHA

52

71-92

68-91

53.85

4W

Chen WQ 2012

CHF

in or out

CMA 2007; NYHA

120

58 ± 14

57 ± 14

59.17

6M

Chen XH 2014

HF

NA

CMA 2014

60

63 ± 10

62 ± 11

52.17

6M

Cheng XD 2013

ischemic heart failure

in

ACC/AHA criteria; NYHA

90

56.4 ± 6.2

54.2 ± 5.9

55.56

6W

Cui LL 2012

CHF

in

CMA 2007; NYHA

68

59.41 ± 9.68

58.6 ± 7.71

48.53

5M

Dai JX 2013

chronic congestive heart failure

NA

Guidelines for the Diagnosis and Treatment of Cardiovascular Disease 2006

100

70.2

58

4W

Ding LB 2010

HF

in

Internal Medicine 2004; MoH 2002

43

45 ± 12.2

42 ± 11.3

55.81

2M

Ding SY 2013

CHF

NA

Practical Internal Medicine 2001; NYHA

72

48-82

51-79

45.83

4W

Dong MX 2013

chronic congestive heart failure

in

Practical Internal Medicine 2001; NYHA

114

71.5

 

59.65

4W

Du YK 2014

diastolic heart failure

out

CMA 2007

102

60-86

59-82

39.22

30D

Duan JH 2010

CHF

NA

Clinical Cardiology 1996

61

63.4 ± 10.3

61.5 ± 8.7

72.13

3M

Fan J 2013a

CHF

NA

Internal Medicine 2008; NYHA

86

68.1 ± 9.5

68.7 ± 9.6

55.81

2M

Feng QT 2013

chronic congestive heart failure

out

Framingham criteria

42

55.6 ± 10.32

54.66 ± 10.41

59.52

6M

Fu JZ 2012

CHF

 

Internal Medicine 2004; NYHA

60

77.3 ± 10.2

78.0 ± 10.1

58.33

3M

Gao JB 2011

chronic congestive heart failure

in or out

MoH 2002

167

58 ± 11

58.08

4W

Gu XM 2009

CHF

in or out

AHA criteria

38

52 ± 9

48 ± 10.6

68.42

2M

Gu XM 2013

CHF

in or out

ACC/AHA 2005; NYHA

65

57 ± 18.5

56 ± 16

66.15

4W

Gu YY 2012

CHF

in or out

NYHA

100

65.5 ± 10.1

62.3 ± 12.5

58.57

6M

Guan SY 2012

CHF

NA

Consensus for diagnosis and treatment of heart failure with normal ejection fraction in China 2010

82

56 ± 13

54 ± 13

42.68

8W

Guan SY 2013

CHF

NA

CMA 2007

72

55 ± 12

54 ± 13

52.78

12W

Guo P 2014

CHF

NA

ACC/AHA criteria; NYHA

90

71.6 ± 4.5

72 ± 3.5

58.7

3M

Guo SL 2011

chronic congestive heart failure

in

CMA 2007

120

60-80

60

3M

Guo WB 2013

chronic congestive heart failure

in

CHF criteria 1979

70

61.5 ± 9.12

57.4 ± 8.97

57.14

8W

Hu B 2013

CHF

in or out

Framingham criteria

80

39-75

36-76

78.75

3M

Huang B 2010

chronic congestive heart failure

NA

Framingham criteria; NYHA

100

61.2 ± 11.8

60.8 ± 12.5

60

6M

Huang YQ 2012

chronic congestive heart failure

NA

Internal Medicine 2004

46

60 ± 7.5

58 ± 7.8

47.83

4W

Huang Z 2014

CHF

in or out

CMA 2007; NYHA

60

35-74

35-74

58.33

12W

Jin Y 2012

heart failure derived from ischemic cardiomyopathy

NA

ICM criteria (Felker GM) 2002; NYHA

100

62.0 ± 15.2

63.0 ± 13.9

47

12W

Jing GJ 2009

CHF

in or out

WHO criteria; CMA 2002; MoH 2002

60

62.0 ± 3.5

63 ± 4.0

58.33

4W

Kuang JB 2008

CHF

NA

ESC criteria

106

71.6

45.16

8W

Li DW 2013

chronic congestive heart failure

in

NYHA

78

66

51.28

12W

Li GM 2011

chronic congestive heart failure

in or out

Framingham criteria; NYHA

120

72.5

71.8

56.67

4W

Li LC 2013

heart failure derived from ischemic cardiomyopathy

NA

NYHA

110

61 ± 13

63 ± 12

54.55

4W

Li P 2011

CHF

in or out

CMA 2002;NYHA

76

66.1 ± 7.8

66.3 ± 7.2

59.21

3M

Li Q 2014

HF

NA

NYHA

120

71.4 ± 8.0

70.2 ± 7.1

70.59

6M

Li RY 2010a

CHF

NA

NYHA

86

68.4 ± 1.3

68.1 ± 1.3

67.44

4W

Li SQ 2014

CHF

in or out

CMA 2007; NYHA

147

41.2 ± 12.5

39.8 ± 13.2

40.82

2M

Li SZ 2009

congestive heart failure

NA

NYHA

39

62 ± 7

56.41

4W

Li T 2010

CHF

in

Boston criteria; NYHA

44

56 ± 14

56.82

4W

Li WY 2013

CHF

NA

Internal Medicine 2008; NYHA

90

71 ± 4.6

73 ± 4.2

57.78

4W

Li XL 2013

CHF

NA

CMA 2007; NYHA

512

56.98 ± 11.59

57.53 ± 11.05

75.36

12W

Li YH 2013

CHF

NA

NYHA

80

67.3 ± 11.6

70

3M

Li YX 2012

diastolic heart failure

in or out

ESC criteria; MoH 2002

100

61.6 ± 5.1

61.4 ± 5.4

43

6M

Li YX 2013

CHF

NA

ESC 2007; MoH 2002;Collateral Disease Theory 2006

80

61.6 ± 5.1

61.4 ± 5.4

46.25

12M

Lin JH 2008

CHF

in or out

Clinical Cardiology 1999; NYHA

80

58 ± 12

60

4W

Lin ZJ 2010

heart failure derived from ischemic cardiomyopathy

NA

WHO/ISFC 1980; NYHA

60

40 ± 13

38 ± 12

45

6M

Liu HL 2008

CHF

NA

Guidelines for Cardiovascular Disease 2005; NYHA

86

32.9 ± 4.1

33.1 ± 3.2

52.33

4W

Liu J 2008

heart failure derived from ischemic cardiomyopathy

NA

WHO/ISFC 1980; NYHA

41

41 ± 11

40 ± 11

60.98

6M

Liu LX 2014

HF

NA

Practical Internal Medicine 2009

60

64.4 ± 11.5

64.5 ± 11.3

61.67

12W

Liu SJ 2009

CHF

in or out

Clinical Cardiology 1996; MoH 2002; NYHA

45

68.2 ± 7.6

66.8 ± 8.2

60

4W

Liu T 2013

HF

NA

NYHA

95

63.7 ± 7.4

65.7 ± 7.6

71.58

4W

Liu TR 2010

CHF

NA

NYHA

84

46-68

45-70

63.1

8W

Liu WJ 2007

ischemic cardiomyopathy

in

Felker's criteria

60

66 ± 10

65 ± 11

70

4M

Liu XC 2008

refractory heart failure

NA

NYHA

120

56-79

58-78

80.83

30D

Liu XC 2011

CHF

in or out

AHA criteria; NYHA

80

56.9 ± 7.3

57.0 ± 7.6

65

8W

Liu XG 2013

CHF

in or out

AHA criteria; NYHA; MoH 2002

60

61.2 ± 11.8

60.8 ± 12.5

58.33

3M

Liu XM 2010

HF

NA

ACC/AHA criteria; NYHA

76

65-82

52.63

3M

Liu XM 2013

CHF

NA

CMA 2007

64

69 ± 11

68 ± 12

57.81

4W

Liu YJ 2012

HF

in or out

Clinical Cardiology; NYHA

60

78-90

76-92

68.33

30D

Long F 2009

CHF

in

Clinical Cardiology 1996; CMA 2002; NYHA

110

20-73

18-70

53.64

4W

Lu JP 2012

CHF

in

CMA 2007; NYHA

60

73.2 ± 12.5

72.9 ± 11.8

65

24W

Luo Q 2013

chronic congestive heart failure

in

NYHA

60

62.5 ± 13.0

64.5 ± 12.2

56.67

3M

Ma AP 2013

CHF

NA

NYHA

96

66.28 ± 4.92

65.84 ± 5.06

56.25

6M

Ma FF 2008a

CHF

in

Boston criteria 1985; NYHA

120

65.4

64.6

46.67

4W

Ma FF 2008b

CHF

in

Boston criteria 1985; NYHA

65

64.1 ± 17.2

46.15

4W

Ma L 2010

CHF

in or out

ESC 1995; NYHA; MoH 2002

117

52.3 ± 9.2

50.1 ± 10.5

61.54

4W

Ma RX 2014

CHF

in

CMA 2007

120

62 ± 12

60 ± 11

65.75

4W

Miao S 2013

HF

NA

NYHA

102

77.2 ± 6.1

100

2M

Niu LY 2012

CHF

NA

ACC/AHA criteria; NYHA; MoH 2002

60

63.2 ± 4.1

60.8 ± 5.4

63.33

4W

Pang XM 2008

CHF

NA

Framingham criteria

31

66 ± 12

48.39

4W

Qiu X 2013

CHF

NA

NYHA

60

62 ± 4.2

60 ± 3.2

66.67

3M

Rao LZ 2012

CHF

NA

CMA 2007; NYHA

80

65 ± 15

64 ± 14

51.25

4W

Shen R 2010

HF

in

NYHA

62

74 ± 5

74 ± 7

77.42

28D

Shen XR 2014

CHF

in or out

ACC/AHA criteria; NYHA

122

62 ± 6

66.45

12M

Shi CP 2013

CHF

in

ISFC/WHO 1979; NYHA

120

64.5 ± 6.2

67.5

3M

Su HM 2007

chronic congestive heart failure

in

Framingham criteria; NYHA 1994

70

55.7

54.6

60

30D

Su LJ 2012

CHF

in or out

CMA 2002; Practical Internal Medicine 2001; NYHA

69

NA

NA

65.22

8W

Su RY 2013

CHF

NA

CMA 2007; NYHA

86

69

46.51

4W

Sun LP 2007

chronic congestive heart failure

in

NYHA

60

62 ± 12

63.33

12W

Tang SY 2013

CHF

in

CMA 2002; Clinical Cardiology 1996; Internal Medicine 2004; NYHA

80

65.4

64.6

47.5

4W

Tao X 2011

CHF

NA

ESC 2008

100

NA

NA

0

4W

Tian Y 2011

diastolic heart failure

NA

ESC criteria; MoH 2002

100

58.0 ± 8.2

58.0 ± 8.5

47

1M

Wang N 2014

CHF

in or out

MoH 2002

54

55-75

58-76

53.7

8W

Wang Q 2012

CHF

in or out

NYHA

80

40-70

41-70

61.25

24W

Wang SZ 2012

HF

NA

Diabetic Cardiomyopathy 2010; NYHA

60

60 ± 13

60 ± 11

61.67

4W

Wang YY 2013

chronic congestive heart failure

in or out

NYHA

79

62.6 ± 2.4

61.4 ± 2.3

53.16

4W

Wei XB 2013

CHF

in

NYHA; ACC/AHA 2009

84

87 ± 6

100

12W

Wen Y 2012

CHF

NA

CMA 2007; NYHA

90

70.4 ± 5.6

57.78

1M

Wu GL 2015

CHF

out

CMA 2007; NYHA

104

67.5 ± 6.8

66.7 ± 7.1

64.32

2M

Wu SP 2014

CHF

in or out

CMA 2014

130

52.2 ± 5.8

53.8 ± 7.3

73.8

4W

Wu Xian 2014

CHF

in

CMA 2007

60

64.47 ± 8.23

63.57 ± 8.94

55.38

4W

Xiong SQ 2014

CHF

in

CMA 2007; NYHA

80

61.2 ± 7.11

62.3 ± 7.45

52.5

6W

Xu GS 2014

CHF

NA

NYHA

64

55.7 ± 14.0

53.6 ± 15.0

59.38

120D

Xue L 2014

CHF

in

A list of clinical manifestation

124

42-86

64.52

8W

Xue LX 2008

chronic congestive heart failure

in or out

AHA criteria

80

56.9 ± 7.3

57.0 ± 7.6

65

8W

Yan KL 2012

CHF

in

Practical Internal Medicine 2009; NYHA

120

65.2 ± 17.5

56.67

12W

Yang DK 2014

CHF

in

NYHA

60

66.0 ± 12.06

65.8 ± 11.33

63.33

4W

Yang F 2007

CHF

NA

ESC 2005

128

66.0 ± 14.0

65.0 ± 15.0

56.25

8W

Yang HT 2012

CHF

in

Clinical Cardiology 1999; NYHA

100

58.5 ± 7.0

59 ± 7.6

57

4W

Yang HT 2013

CHF

in

Clinical Cardiology 1999

100

58.5 ± 7.0

59 ± 7.6

57

4W

Yang J 2013

CHF

NA

CMA 2007; NYHA

90

56.8 ± 4.3

C1 (57.2 ± 4.1) C2 (57.1 ± 3.9)

43.33

12W

Yang W 2012

CHF

in

CMA 2007; NYHA

80

60.52 ± 12.6

62.7 ± 9.6

56.25

4W

Yao L 2011

CHF

in

CMA 2007; NYHA

102

52 ± 11

56 ± 9

52.94

8W

Ye RS 2013

CHF

NA

CMA 2007; NYHA

80

65-92

65-90

56.25

6M

Ye S 2012

CHF

in

CMA 2007; NYHA

114

60.29 ± 5.62

53.51

3M

Yin ZL 2009

congestive heart failure

in

Framingham criteria; NYHA

50

57.4 ± 7.6

66

4W

Ying M 2013

CHF

NA

Framingham criteria; NYHA

80

50-80

52.5

3M

Yu JH 2008

diastolic heart failure

in

Framingham criteria; CHFA 2001; NYHA

70

65.7 ± 6.1

66.1 ± 8.2

60

12M

Yuan JK 2012

HF

in

NYHA

62

41.65 ± 9.33

43.08 ± 7.55

58.06

4W

Zhai N 2015

CHF

NA

CMA 2014

80

70.6 ± 4.4

61.54

12W

Zhang CA 2013

CHF

in or out

AHA 1995; NYHA

83

59.31 ± 10.19

61.0 ± 8.39

66.27

12W

Zhang H 2011

CHF

NA

ISFC/WHO criteria

123

45-80

50-82

60.16

4W

Zhang J 2015

CHF

NA

Practical Internal Medicine 1998,NYHA

60

63.1 ± 9.5

62.5 ± 8.2

50

4W

Zhang R 2014

CHF

in

CMA 2007; NYHA

80

55.0 ± 10.9

53.0 ± 11.3

62.14

8W

Zhang WL 2013

CHF

in

NYHA

94

47-86

45-87

58.51

4W

Zhang XX 2010

left cardiac insufficiency

NA

NYHA

136

53.5

52.94

6M

Zhao JS 2014

CHF

NA

CMA 2007; NYHA; MoH 2002

450

54.8 ± 4.6

55.3 ± 4.7

48.33

12W

Zhao MJ 2009 &Zhao MJ 2012

HF

in or out

Framingham criteria; NYHA

68

46-69

45-69

64.71

4W

Zheng JJ 2012

CHF

in

CMA 2007; NYHA

76

64 ± 15

64 ± 14

55.26

6M

Zheng LW 2013

CHF

in or out

CMA 2007; NYHA

164

66.9 ± 11.5

67.8 ± 12.0

53.05

12W

Zheng WH 2014

refractory heart failure

NA

NYHA

87

63.44 ± 2.20

61.92 ± 2.70

56.32

6W

Zhou FZ 2011a

congestive heart failure

in

NYHA

59

66

69.49

12W

Zhou Y 2013

HF

NA

Internal Medicine 2010

60

56.9 ± 7.3

57.0 ± 7.6

63.33

8W

Zhu HG 2012

CHF

in or out

NYHA

78

63.1

63.4

61.54

3M

Zhuo JY 2013

CHF

NA

NYHA

136

62.74 ± 7.78

61.01 ± 8.12

54.41

4W

ACC American College of Cardiology, AHA American Heart Association, C control group, CHF chronic heart failure, CHFA Chinese Heart Failure Association, CMA Chinese Medical Association, ESC European Society of Cardiology, HF heart failure, ISFC International Society and Federation of Cardiology, ISH International Society of Hypertension, MoH Ministry of Health in China, NA not available, NYHA New York Heart Association, T treatment group, WHO World Health Organization

Methodological quality of included trials

The methodological quality of included trials was generally low as most failed to provide protocols (Additional file 3). Nineteen trials (n = 2388 participants, 20.68 %) were judged as low risk on random sequence generation. Of these twenty, 17 trials used random number tables (n = 1774 participants, 72.29 %), one trial used statistical software (n = 512 participants, 21.44 %) and one trial used drawing lots. Only one (Li XL 2013) trial reported allocation concealment was judged as low risk; one trial (Yang F 2007) described using an envelope but failed to provide further details and was subsequently judged as presenting with unclear risk of bias.

We judged five trials on the use of blinding methods. Of these, three double-blind placebo controlled trials (Yu JH 2008, Li XL 2013, Yu JH 2008) were judged as low risk (n = 702 participants, 6.08 %). For the remaining two trials, one single-blind trial (Guo WB 2013) and one double-blind trial (Wei XB 2013) did not mention who was blinded and were judged as unclear risk. Besides, only one trial (Li XL 2013) reported the blinding of outcome assessment (n = 512 participants, 4.43 %).

Overall six trials reported patient attrition (n = 948 participants, 8.21 %). Of these, three trials (Chen WQ 2012, Fu JZ 2012, Sun LP 2007) reported no drop-out. Three trials (Guo P 2014, Li XL 2013, Kuang JB 2008) described the occurrence of attrition, one (Li XL 2013) used a flow chart to describe patient attrition in the two parallel groups throughout the whole study and adopted intention to treat (ITT) analysis, and one (Kuang JB 2008) was judged as high risk as the authors failed to provide drop-out reasons in text. The remaining trials reported the same number of participants between the baseline and data analyzed, except one study (Guo WB 2013) which reported six cases less than the number at baseline without providing further explanation.

Twenty-four trials failed to report all outcomes listed in the methods. The remaining trials reported all outcomes as specified in methods, although only one provided a study protocol. Insufficient information was available for us to conduct a risk of bias assessment in terms of selective reporting. In terms of other biases, only 122 trials reported comparability of baseline data and only one study (Li XL 2013) reported conducting a sample size calculation (Fig. 2).
Fig. 2

Risk of bias summary

Effects of interventions

Qili Qiangxin capsule plus conventional treatment versus conventional treatment

Our meta-analysis (Additional file 4) showed that in comparison to conventional treatment alone, Qili Qiangxin plus conventional treatment did not have a statistically significant effect on reducing mortality (RR 0.53, 95 % CI 0.27 to 1.07, I2 = 0 %). Qili Qiangxin plus conventional treatment led to a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64, I2 = 0 %; defined as outpatient visits or re-admission for HF and cardiogenic or all-cause mortality), when separately analyzed, it significantly reduced the outpatient visits (n = 1 trial, 60 participants, RR 0.22, 95 % CI 0.05 to 0.94), but did not have a statistically significant effect on reducing cardiogenic mortality (n = 1 trial, 56 participants, RR 0.67, 95 % CI 0.21 to 2.11). Meta-analysis showed a statistically significant reduction in hospitalizations due to HF (RR 0.49, 95 % CI 0.38 to 0.64, I2 = 0 %), and in addition, sensitivity analysis based on consideration of ‘worst-case’ scenarios revealed that missing data did not change the result of this meta-analysis (RR 0.50, 95 % CI 0.39 to 0.65, I2 = 0 %). Besides, due to the limited quantity of trials reported major outcomes, we did not carry out subgroup analyses on different types of heart failure or different durations of treatment.

In addition, when compared with conventional treatment alone, Qili Qiangxin plus conventional treatment significantly improved cardiac function (RR 1.38, 95 % CI 1.29 to 1.48, I2 = 0 %; defined as an increase of two or more functional classes using NYHA) and QOL (MD −8.48 scores, 95 % CI −9.56 to −7.39, I2 = 24 %). Used as an adjunctive treatment, Qili Qiangxin was associated with a lower incidence of adverse events (RR = 0.56, 95 % CI 0.40 to 0.78, I2 = 19 %). Details are displayed in Table 2.
Table 2

Summary of findings of Qili Qiangxin plus conventional treatment compared to conventional treatment for heart failure

Outcomes

Illustrative comparative risksa (95 % CI)

Relative effect (95 % CI)

No of Participants (studies)

Quality of the evidence (GRADE)

Comments

Assumed risk

Corresponding risk

Conventional treatment

Qili Qiangxin plus Conventional treatment

    

All-cause mortality or cardiovascular mortality

72 per 1000

38 per 1000 (20 to 77)

RR 0.53 (0.27 to 1.07)

539 (6 studies)

lowb,c,d

 

Follow-up: 1 to 6 months

Major cardiovascular events

598 per 1000

275 per 1000 (203 to 383)

RR 0.46 (0.34 to 0.64)

224 (3 studies)

moderateb,d

 

Follow-up: 3 to 6 months

Hospitalizations due to heart failure

342 per 1000

167 per 1000 (118 to 223)

RR 0.49 (0.38 to 0.64)

669 (9 studies)

moderateb

 

Follow-up: 1 to 6 months

cardiac function (defined as an increase of two or more functional classes using NYHA)

336 per 1000

464per 1000 (434 to 498)

RR 1.38 (1.29 to 1.48)

4603 (54 studies)

lowb,e

 

Follow-up: 1 to 6 months

Quality of life (QOL)

 

The mean QOL in the intervention groups was 8.48 lower (9.56 to 7.39 lower)

 

792 (10 studies)

lowb,f

 

Follow-up: 1 to 12 months

Adverse drug reaction (ADR)

35 per 1000

20 per 1000 (14 to 27)

RR 0.56 (0.40 to 0.78)

4846 (56 studies)

moderateb

 

Patient or population: patients with heart failure

Settings: in or out

Intervention: Qili Qiangxin plus Conventional treatment

Comparison: Conventional treatment

CI confidence interval, RR risk ratio

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate

Very low quality: We are very uncertain about the estimate

aThe basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95 % confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95 % CI)

bThe RCTs failed to reported the methods of randomized and concealment of allocation

cThis outcome is a clinical endpoint

dTotal number of events is less than 300

eMost of the trials have wide range of 95 % CI for effect estimate

fThere was significant statistical heterogeneity among trials according to I 2 test

A total of 84 trials evaluated LVEF and were pooled with a random model. Pooled comparisons demonstrated that Qili Qiangxin plus conventional treatment had a statistically significant beneficial effect compared to conventional treatment alone in terms of LVEF (MD 5.87, 95 % CI 5.28 to 6.47). However, a significant degree of heterogeneity was detected (I2 = 91 %), and when take subgroup analysis on duration of treatment, large heterogeneity still existed. Tests for subgroup differences showed no significant difference in effect between the trials with different treatment duration. Meta-analysis of 24 trials demonstrated that Qili Qiangxin plus conventional treatment significantly reduced levels of NT-proBNP (MD −214.43 pg/ml, 95 % CI −269.42 to −159.45). The high level of heterogeneity (I2 = 96 %) in these trials however should be noted. Similarly, pooled comparison of 42 trials indicated that Qili Qiangxin plus conventional medicine significantly improved the 6MWD (MD 47.21 meters, 95 % CI 44.53 to 49.90) when compared with conventional medicine alone. Again, a considerable level of heterogeneity (I2 = 96 %) was observed.

Considering general low quality of included trials, we did not take sensitivity analyses based on study quality according to protocol.

Qili Qiangxin capsule plus conventional treatment versus placebo plus conventional treatment

Three trials were identified for this comparison. One multicenter double-blind trial (Li XL 2013) evaluated the composite cardiac events (CCEs) for 491 patients, and reported that CCE rate was 4.51 % in the Qili Qiangxin plus conventional treatment group, compared with 10.93 % in the placebo plus conventional treatment group (p < 0.05) [18]. This study also reported a favorable effect of Qili Qiangxin plus conventional treatment on the plasma NT-proBNP level, the NYHA functional classification and QOL by MLHFQ at 12 weeks (p < 0.001 for above outcomes). Meta-analysis of three trials (Fig. 3) showed statistically significant improvement of 6MWD in the Qili Qiangxin plus conventional medicine group compared to placebo plus conventional medicine (MD = 49.55 meters, 95 % CI 38.79 to 60.32, I2 = 0 %).
Fig. 3

Forest plot of Qili Qiangxin plus conventional treatment versus placebo plus conventional treatment

Qili Qiangxin capsule plus conventional treatment versus medications recommended in guidelines plus conventional treatment

Nine trials compared Qili Qiangxin capsule plus conventional treatment to supplementary medications recommended in clinical guidelines. The supplementary medications included thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, trimetazidine, hydrochlorothiazide and digoxin.

Meta-analysis with a fixed model of four trials indicated no significant effect on cardiac function (RR = 1.26, 95 % CI 0.94 to 1.70, I2 = 4 %) for Qili Qiangxin plus conventional treatment when compared with supplementary medications plus conventional treatment. Further subgroup analyses on cardiac function according to medications found that Qili Qiangxin had no statistically significant differences compared to captopril (n = 2 trials, RR = 1.27, 95 % CI 0.89 to 1.82, I2 = 0 %), irbesartan plus trimetazidine (n = 1 trial, RR = 2.50, 95 % CI 0.83 to 7.49), or digoxin (n = 1 trial, RR = 0.85, 95 % CI 0.45 to 1.59).. Meta-analysis with a random model of four trials showed that Qili Qiangxin plus conventional treatment had significantly lower risk of adverse events (RR = 0.21, 95 % CI 0.06 to 0.74, I2 = 49 %). Two trials reported 6MWD and meta-analysis showed that Qili Qiangxin plus conventional treatment significantly improved 6MWD compared with supplementary medications (MD = 43.29 meters; 95 % CI =14.91 to 71.67, I2 = 58 %).

Publication bias

A funnel plot analysis was generated for 50 trials comparing Qili Qiangxin plus conventional treatment to conventional treatment alone for the outcome of NYHA levels. No asymmetry was observed, suggesting no publication bias (Fig. 4).
Fig. 4

The funnel plot of publication bias

Discussion

Summary of findings

The findings of this review suggest that in patients with HF, Qili Qiangxin used as an adjunct to conventional treatment leads to a statistically significant reduction in major cardiovascular events and re-hospitalization due to HF when compared with conventional treatment alone. However, there appeared to be no additional effects of Qili Qiangxin in terms of mortality rate. Qili Qiangxin plus conventional treatment also appears to significant improvements in cardiac function measured by levels of NHYA and showed significant beneficial effects on NT-proBNP levels, QOL, LVEF and 6MWD. Pooled data indicated that Qili Qiangxin as an adjuvant treatment have clinical significance in improving exercise capacity as well as symptomatic status. Preliminary data suggests that Qili Qiangxin appears to be safe. However, it should be noted that the majority of included trials had low methodological quality and a high risk of bias. Any conclusions drawn from this review should therefore be interpreted with caution.

Strength and limitations

This study presents the first comprehensive and rigorous review of Qili Qiangxin as a supplementary treatment for patients with HF. Previous criticisms have been made regarding the use of different terms to describe types of HF potentially being confusing [7]. It is strength of this review that we included all types of HF with different comorbidities in order to maximize the impact and clinical relevance of our findings.

There are a number of limitations to this review which need to be acknowledged. The majority of included studies were assessed as unclear risk of bias. This was largely owing to the lack of details, particularly in terms of random sequence generation, allocation concealment, blinding methods and availability of a protocol. Due to limited resources and time constraints we were not able to contact trial authors to request missing data and other information preventing us from being able to make a complete assessment regarding risk of bias. However, the sensitivity analysis indicated that the missing data not change the results in this review. Furthermore, the follow-up period in the included studies was no longer than six months, with the majority reporting a follow-up of three months or less. This makes it difficult to interpret the present evidence on mortality as an outcome, and in assessing the long-term effects and safety of administering Qili Qiangxin. We excluded 40 articles on the basis of no relevant outcomes reported. These articles did not report the outcomes we listed in protocol, instead, they chose composite outcome indicator. We excluded these articles as they failed to provide data of separate components. Considering all studies excluded for this reason reported positive results for the composite outcome, we believed the exclusion was unlikely to affect the results of our review.

Previous studies

A recent editorial has suggested that Qili Qiangxin showed promising results. If Qili Qiangxin is shown to be safe and effective from further rigorous clinical trials research, this presents an interesting area of further work that may fundamentally challenge our current need to precisely understand the pharmacodynamics of all drug therapies [19]. Herbal medicines appear to operate through a variety of often poorly defined synergistic mechanisms involving multiple chemical components. In our study we found that Qili Qiangxin capsules have a positive effect on NT-proBNP levels. Previous studies showed that NT-proBNP level can be used as a prognostic marker for congestive heart failure as decreased NT-proBNP levels predicted reducing mortality in 10 years [2022]. Levels of NT-proBNP clearly differ among various congenital heart lesions, and a higher level of NT-proBNP correlates with diastolic dysfunction parameters. NT-proBNP levels are related to exercise capacity and also increase with the more dysfunctional HF stages [23]. In our study, we included patients regardless of gender, age, etiology, ethnic group, severity, and course of diseases. Consequently the patients’ in different trials had different underlying diseases. All of these factors might explain the high heterogeneity in the meta-analysis of NT-proBNP. The high heterogeneity of LVEF and 6MWD might separately due to the different population baseline of LVEF and 6MWD in the included trials.

Implications for future research

The results from this review suggest that further research is warranted in order to provide further evidence assessing the effects and safety of Qili Xiangxin as an adjuvant to conventional treatments for HF. We have a number of recommendations for future research. Various diagnostic criteria are used internationally for HF and future research should ideally use internationally recognized diagnostic criteria such as the ACC/AHA guidelines or ESC guidelines as part of their inclusion criteria. Further studies of Qili Qiangxin should also incorporate a minimum one year follow-up period in order that clinically important data on outcomes such as mortality and cardiac events can be provided. These were rarely reported amongst the RCTs we found in this review and further data in this area would be clinically meaningful to patients and providers. Furthermore, we found the reporting of clinical trial methods such as random sequence generation and allocation concealment inadequate and we recommend researchers report in full their trial methodology in future publications. Linked to this, none of the RCTs we included in this review provided trial protocols, and some did not provide all outcomes that had been described in the methods section. For transparency, we recommend that researchers prospectively register trials, publish trial protocols and cite the protocol or registration number in subsequent publications. This will enable future researchers and guideline developers to consider the evidence presented in light of what had been planned by the research team prior to trial commencement. Finally, we found few RCTs using placebo-control design in this review. Studies in future should adopt a double-blinded placebo-controlled design in order that further information regarding specific effects of Qili Qiangxin in HF can be provided.

Conclusions

When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. Qili Qiangxin appeared to be associated with an increased QOL and preliminary data suggested that it is safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further rigorous research is warranted through large, prospective clinical trials in order to confirm these findings.

Declarations

Acknowledgements

We would like to thank Dr. Jin Luo for her professional advice.

Funding

This study was supported by the Program for Innovative Research Team (2011-CXTD-09) of Beijing University of Chinese Medicine, the grant of Research Capacity Building (No. 201207007) from the State Administration of Traditional Chinese Medicine of China. GY Yang and JP Liu was were partially funded by grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health (www.nccam.nih.gov).

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article.

Authors’ contributions

JS designed the study, performed the study and drafted the manuscript: KZ extracted and analyzed the data, and participated in the revise of the manuscripts. WJX extracted the data and prepared graphs, GYY helped to analyze the data and revised of the manuscript. YJZ extracted the data, CCW participated in extracting data. LL helped to revise the manuscript and corrected language problems. MH helped to revise the manuscripts. GL helped to correct language problems. JPL conceived of and designed the study and helped to draft the manuscript. All authors read and approved the final manuscript.

Competing interest

The authors declare that they have no competing interest.

Consent to publish

Not applicable.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine
(2)
Complementary and Integrated Medicine Research Unit, Primary Care and Population Sciences, University of Southampton
(3)
National Research Centre in Complementary and Alternative Medicine (NAFKAM), Faculty of Health Sciences, UiT The Arctic University of Norway

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Copyright

© The Author(s). 2016

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