Chronic pulmonary heart disease (CPHD) is a rising major public health problem worldwide [
The eligibility criteria for conducting the survey included administration of ligustrazine hydrochloride injection for the treatment of CPHD and duration of treatment and also included trials involving patients of any age, sex, or CPHD stage. However, we excluded pharmacokinetic studies, nonrandomized evaluations, and animal/laboratory studies.
Two reviewers (L. S. Y. and W. Z. W.) identified relevant randomised controlled trials independently, including all languages, by a systematic search of PubMed (1990–2010), Chinese Biomedical Database (CDROM, 1990–2010), EMBASE (1990 to December 2010), AMED (1990 to December 2010), Chinese BioMedical Literature Database (CBM, 1990 to December 2010), the Cochrane Library (Issue 2, 2010), and BIOSIS (1997 to 2008). With the following terms: (cor pulmonale or chronic pulmonary heart disease) AND (Ligustrazine hydrochloride injection or ligustrazine hydrochloride injection). We used the wild card term “*” to enhance the sensitivity of our search strategy. Reviewers scanned the bibliographies of all retrieved trials and other relevant publications, including reviews and meta-analyses, to ensure a thorough search.
Two reviewers (L. S. Y. and L. Y.) extracted data and evaluated data’s quality and content independently. We conducted data extraction using a standardized procedure. Initially, abstracts were screened to exclude obviously ineligible reports, and then all remaining articles were reviewed. We classified trials and abstracts according to drug, patient characteristics, study design, and therapy duration. Reviewing study design included the following criteria: methods of sequence generation, allocation concealment, complete description of those who were blinded [
The primary outcome measures included (1) New York Heart Association classification (NYHA) of clinical status; (2) adverse events. The secondary outcome measures included (1) death, (2) hemodynamics, (3) quality of life as measured by various instruments.
The data was entered into an electronic database by the two reviewers separately, avoiding duplicate entries; in the case where the two entries did not match, an inspection will be conducted, and a third person may be involved for verification. In order to obtain full information regarding conference abstracts, we had contacted the study authors by email and/or telephone communication.
The statistical package (RevMan 5.0) provided by the Cochrane Collaboration was used to analyze the data. Dichotomous data was presented as Odds Ratio (OR), with 95% confidence intervals (CIs). Continuous outcomes were presented as weighted mean difference, with 95% CI. Analyses were performed by intention-to-treat where possible. Otherwise, for dichotomous outcomes, patients with incomplete or missing data were included in sensitivity analyses by counting them alternately as treatment failures or successes. For continuous variables we used simple sensitivity analysis to test how robust the results were under different assumptions about what might have happened to patients with missing data.
Meta-analysis was only performed within comparisons where individual trials were compared with similar treatment and control interventions.
An initial search identified 337 potentially relevant articles. A total of 245 articles were initially excluded because of duplicate publication, and then 35 articles were excluded because they did not meet our inclusion criteria. From the identified 57 potentially eligible reports, 23 articles out of 57 were excluded for further assessment. The most frequent reasons for exclusion were other types of intervention examined, either no clinical outcomes reported, or not a randomized trial so that a total of 34 studies (2319 participants) were included into the review. All studies were published in Chinese. Figure
Characteristics of included studies.
Included studies | Methods | Participants | Interventions | Outcomes | |||||||||
Date of study | First author | Double-blind | Settings | Age (years) | Gender | Experiment group | Control group | Death | Clinical status | Quality of life | Hemorheology | Adverse effect | |
1999 | Chen | Yes | H | 72/52 | 45–85 | M, F | Conventional medicine treatment plus ligustrazine injection 200–240 mg qd. 14 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2010 | Chen | No | H | 46/46 | 61–77 | M, F | Conventional medicine treatment plus ligustrazine injection 100 mg qd. 14 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2010 | Yuan | No | H | 31/31 | NK | M, F | Conventional medicine treatment plus Ligustrazine Hydrochloride injection 40 mL, 60 mL qd. 14 days | Conventional medicine treatment | No | Yes | No | Yes | NK |
2009 | Bai | No | H | 35/35 | 58–80 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg qd. 14 days | Conventional medicine treatment | No | Yes | No | Yes | No |
2009 | An | No | H | 40/38 | 59–81 | M, F | Conventional medicine treatment plus ligustrazine injection 120 mg qd. 14 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2009 | Hao | No | H | 50/50 | 55–75 | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2009 | Wu | No | H | 30/30 | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | NK | |
2009 | Wu | No | H | 40/40 | 50–70 | M, F | Conventional medicine treatment plus ligustrazine injection 800 mg qd. 7 days | Conventional medicine treatment | NK | No | No | No | NK |
2009 | Ma | No | H | 36/36 | 48–82 | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg qd. 14 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2008 | Li | No | H | 31/30 | M, F | Conventional medicine treatment plus ligustrazine injection 100 mg qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | NK | |
2008 | Liu | No | H | 38/36 | Mean 65.2/65.6 | M, F | Conventional medicine treatment plus ligustrazine injection 120–240 mg qd. 10 days | Conventional medicine treatment | NK | Yes | No | Yes | NK |
2008 | Qi | No | H | 34/30 | 57–82 | M, F | Conventional medicine treatment plus ligustrazine injection 100 mL. qd 14 days | Conventional medicine treatment | No | Yes | No | Yes | NK |
2008 | Ye | No | H | 32/32 | M, F | Conventional medicine treatment plus ligustrazine injection 120 mg. qd 10 days | Conventional medicine treatment | No | Yes | No | No | No | |
2008 | Xie | No | H | 56/49 | 36–75 Mean 66.5/38–77 Mean 67 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd or bid. 10–14 days | Conventional medicine treatment | NK | Yes | No | Yes | NK |
2007 | Fan | No | H | 22/21 | M, F | Conventional medicine treatment plus Ligustrazine Hydrochloride injection 100 mL. qd. 14 days | Conventional medicine treatment | No | Yes | No | Yes | Yes | |
2007 | Sun | No | H | 40/40 | 63.67 ± 14.15/67.25 ± 10.64 | M, F | Conventional medicine treatment plus Ligustrazine Hydrochloride injection 160 mg. qd. 14 days | Conventional medicine treatment | NK | Yes | No | Yes | NK |
2006 | Shui | No | H | 31/28 | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg. qd. 7 days | Conventional medicine treatment | NK | Yes | No | Yes | NK | |
2006 | Wei | No | H | 29/22 | 59–81 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd. 7 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2006 | Zhu | No | Out patient | 12/12 | 47–85 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | No |
2006 | Wang | No | H | 120/80 | 40–85 | M, F | Conventional medicine treatment plus ligustrazine injection 100 mg. qd. 10–15 days | Conventional medicine treatment | NK | Yes | No | Yes | NK |
2006 | Xu | No | H | 36/34 | 56–82, | M, F | Conventional medicine treatment plus ligustrazine injection 160 mg. qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | NK |
2005 | Huang | No | H | 30/30 | 49–71 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd. 10 days | Conventional medicine treatment | Nk | Yes | No | No | Nk |
2005 | Liu | No | H | 30/30 | 59–75, | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg. qd. 10–14 days | Conventional medicine treatment | NK | Yes | No | Yes | No |
2005 | Pan | No | H | 16/16 | 60–89 | M, F | Conventional medicine treatment plus ligustrazine injection 160 mg. qd. 14 days | Conventional medicine treatment | NK | Yes | No | Yes | NK |
2004 | Gao | No | H | 23/20 | 55–80 | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd. 15 days | Conventional medicine treatment | Yes | Yes | No | No | No |
2004 | Ma | No | H | 30/30 | 50–70 | M, F | Conventional medicine treatment plus ligustrazine injection 800 mg. qd. 7 days | Conventional medicine treatment | No | Yes | No | No | NK |
2004 | Zhang | No | H | 30/25 | 53–79 | M, F | Conventional medicine treatment plus ligustrazine injection 200 mg. qd. 10 days | Conventional medicine treatment | No | Yes | No | No | NK |
2003 | Liu | No | H | 26/26 | 56–82 | M, F | Conventional medicine treatment plus ligustrazine injection 200 mg. qd. 14 days | Conventional medicine treatment | No | Yes | No | Yes | NO |
2001 | Xia | No | H | 47/41 | 58–73 | M, F | Conventional medicine treatment plus ligustrazine injection 200–240 mg. qd. 14 days | Conventional medicine treatment | NK | Yes | No | No | No |
2001 | Zhu | No | H | 30/30 | stratified | M, F | Conventional medicine treatment plus ligustrazine injection 800 mg. qd. 10 days | Conventional medicine treatment | Yes | Yes | No | Yes | No |
2000 | Sun | No | H | 36/36 | NK | M, F | Conventional medicine treatment plus ligustrazine injection 400 mg. qd. 14 days | Conventional medicine treatment | No | Yes | No | No | NK |
1994 | Wang | No | H | 26/26 | 37–77 | M, F | Conventional medicine treatment plus ligustrazine injection 160 mg. qd. 10 days | Conventional medicine treatment | NK | No | No | No | No |
2008 | Zhou | No | H | 49/47 | NK | M, F | Conventional medicine treatment plus ligustrazine injection 80 mg. qd. 10 days | Conventional medicine treatment | NK | Yes | No | No | No |
H: hospital; M: male; F: female; NK: not known.
The Quality of Reporting of Meta-analyses flow diagram for the meta-analysis.
The age of patients in the included studies ranged from 37 to 85 years old. Most trials included more males (54% to 89%) than females; only 1 trial included more females (55%). All included trials applied standard western medicine diagnostic criteria for CPHD, although some trials also used TCM criteria in addition. The dose range of ligustrazine hydrochloride injection was from 60 mg to 800 mg and dose route was intravenous injection in all included studies. The total duration of treatment varied from 7 to 15 days.
None of the trials have undergone assessment of patients’ routine living ability after treatment; some trials had measurement of blood gas analysis and hemodynamic parameters.
Only ligustrazine injection was studied in these included trials. None of the trials was randomized, double-blind, placebo controlled. All included trials were designed to compare ligustrazine hydrochloride injection plus conventional treatment with the conventional treatment alone.
The methodological quality of most included trials was generally “poor.” No trials reported using randomization method, yet only 1 trial mentioned double-blind [
Although we conducted comprehensive searches and tried to avoid bias, since all trials were published in Chinese, we could not exclude potential publication bias.
32 trials (2319 patients) concluded an improvement in heart failure [
Comparison of ligustrazine hydrochloride injection + conventional treatment versus conventional treatment. Lack of improvement in heart failure (NYHA class improved <I class or worsening of heart failure). M-H: Mantel-Haenszel formula.
No obvious adverse events occurred in 21 trials, and no adverse events were reported in 11 trials. One trial reported adverse events [
Deaths were reported in only 3 trials [
Comparison of death rate in ligustrazine hydrochloride injection + conventional treatment versus conventional treatment.
Two trials provided data for Doppler echocardiography hemodynamic change [
Three trials showed a significant decrease mean pulmonary arterial pressure (WMD −4.77, 95% CI −5.85 to −3.68) [
Comparison of mean pulmonary arterial pressure in ligustrazine hydrochloride injection + conventional treatment versus conventional treatment. SD: standard deviation.
No trial assessed quality of life.
In many years, western medicine has made great progress and had become the dominating and leading medical treatment research and development worldwide. However, it has been increasingly recognized that western medicine may sometimes fail to treat any illness, whereas such illness is reportedly improved by the so-called complementary and alternative medicine based on a different theory. Few relevant articles on TCM for CPHD have been published in the English medical journals, and the limited evaluation of TCM beyond China reduces its external validity.
This review of randomized trials shows the current evidence in ligustrazine injection for CPHD. Treatment was applied according to a diagnosis of CPHD without further syndrome differentiation according to traditional Chinese methodology. Study sizes were generally insufficient. All conclusions, therefore, were impropriate. There were no descriptions of allocation concealment and no assurances that blinding was maintained. The type of conventional medicine used and the dosages were often impropriate reported, so it was not certain that all studies used similar medications.
Ligustrazine injection plus conventional medicine treatment showed significantly less outcomes of decreased heart function as with “no change or worse” in comparison with the treatment of conventional medicine alone. With measurement using NYHA of clinical status (OR, 0.22; 95% CI, 0.17 to 0.28), the treatment group had, on average, 22 percent less than those treated with conventional medicine alone. These results were positively encouraging and promising of combining ligustrazine injection with conventional treatment, which might be beneficial to heart function. The positive findings were also observed in mean pulmonary arterial pressure outcome (WMD −4.77, 95% CI −5.85 to −3.68). In our opinion, such an average difference would be noticeable and clinically meaningful. In addition, patients treated with ligustrazine injection may have a beneficial effect on cardiac output, ejection fraction, and stroke volume, however, there is just one study providing this result. As for other outcomes, such as death, there were just 3 trials (total
Adverse effects were reported by Shaodong and Xuefen (2007) [
The application of traditional Chinese herbal medicine is fundamentally prescribed with syndrome differentiation. Failure to apply syndrome differentiation may result in treatments being ineffective or even harmful. Despite this, there is some evidence that these Chinese herbal medicines, combined with conventional medicine and given in a way that is not in keeping with their normal use within traditional Chinese medicine, may be beneficial for people with CPHD across a range of outcomes. If these medicines are used properly the positive effects could be enhanced.
The improvement of heart failure was noticed in the survey; however, the effects may not be true due to improper study design or method used, such as lack of randomization or allocation concealment. Publication bias could also be a factor. we tried to take all measures to contact authors to get further information either by telephone, letter, or email. Unfortunately, we got no replies, and we are not sure, the trials were conducted as true RCT. Subsequently, no clear conclusion could be made from these trials.
In conclusion, because of the unclear methodological quality of these identified trials, a definite conclusion on efficacy and adverse events associated with ligustrazine injection cannot be drawn from this review. We found no evidence of a beneficial effect on the primary measure of efficacy to support the routine use of ligustrazine injection for CPHD. However the drug appeared to have no major adverse effects, and if its positive effects were confirmed by comprehensive clinical trials, it would lead to many promising treatments for CPHD and could benefit all patients all over the world. Therefore, further thorough investigation, large-scale, proper study design, randomized trials of ligustrazine injection for CPHD will be required to justify the effects reported here. Future trials should overcome the limitations of the trials presented in this review; particularly, they should assure adequate concealment of allocation and blinding of outcome assessors and use functional outcome as the primary outcome measured at long-term followup. Reports of the trials should conform to the recommendations of the CONSORT statement. If reliable RCT results confirmed ligustrazine injection’s positive effects for treatment of CPHD, it would be blessing news for CPHD patients worldwide.
This paper is supported by the National Program on Key Basic Research Project (973 Program) (Grant no. 2006CB504605) and the Program for New Century Excellent Talents in the University of HeNan Province (Grant no. 2006HANCET-05). Li Jian-sheng and W. Hai-feng are contributing equally to this work.