Accepted Manuscript Title: The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: A systematic review and meta-analysis of randomized controlled trials Author: Lei Yu Yongjie Qin Qingqing Wang Lu Zhang Yaqiong Liu Taiwu Wang Lan Huang Long Wu Hongyan Xiong PII: DOI: Reference:
S0965-2299(14)00065-X http://dx.doi.org/doi:10.1016/j.ctim.2014.05.001 YCTIM 1339
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
22-4-2013 23-4-2014 3-5-2014
Please cite this article as: Yu L, Qin Y, Wang Q, Zhang L, Liu Y, Wang T, Huang L, Wu L, Xiong H, The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: A systematic review and metaanalysis of randomized controlled trials, Complementary Therapies in Medicine (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Introduction: Ischemic heart disease (IHD), which is synonymous with the term “coronary heart
ip t
disease”, is the leading cause of death in the world1. It is defined as myocardial impairment due to an imbalance of coronary blood flow and myocardial impairment
cr
caused by changes in the coronary circulation. IHD can be classified into different
us
categories: Primary cardiac arrest, Angina pectoris, Myocardial infarction, Heart failure in IHD and Arrhythmias. Angina pectoris is the main clinical symptom seen in
an
IHD patients, and it is characterized by discomfort in the chest, jaw, should, or arm2-3. The most common treatment of IHD uses western medicines, mainly nitrate esters,
M
statins and platelet inhibitors. It is thought that though western medicines have rapid onset and are effective and reliable, their long-term use is associated with side effects
te
d
and risk of developing drug resistance due to long-term use. Compared with western medicine, traditional Chinese medicines used for treating IHD have low toxicity
Ac ce p
and fewer side effects.
Rhodiola (Crassulaceae) is a famous genus of medicinal herbs in China. In
traditional Chinese medicine, Rhodiola species have been used as a tonic, hemostatic, or antibechic agent for treatment of leucorrhea, contusion, cold/flu-like symptoms and maintain healthy cardiovascular function4. Phytochemical studies have revealed that
the main bioactive compounds, salidroside (SAL) and tyrosol (TYR) are similar to those used in modern medicine for improving cardiovascular function. These compounds exert pharmacological effects, such as enhancing myocardial contractility, increasing myocardial contraction and inducing hypotension in laboratory animals5-7.
Page 1 of 29
Based on the traditional Chinese medicine theory and the cardioprotective effects of
pharmacology,
Rhodiola
formulations
such
as
Nuodikang
capsule,
ip t
Dazhuhongjingtian injection, Dazhuhongjingtian capsule and other Rhodiola medicines have been used for a long time to treat IHD, and many clinical studies
cr
published in Chinese language have claimed that Rhodiola formulation can relieve the
us
symptoms of IHD. However, there has been no systematic review to assess the effects and safety of Rhodiola formulations. The aims of this systematic review were to
an
summarize and critically evaluate the effects of different Rhodiola formulations on treating IHD, both as a sole agent and in combination with other drug regimens.
M
Methods Sources of information
te
d
Clinical trials were searched and retrieved from major electronic databases including: PubMed, Science Direct, the Cochrane Library, China National Knowledge
Ac ce p
Infrastructure (CNKI), China Master Theses Full-text Database (CMTD), China Doctor Dissertations Full-text Database (CDMD), Chinese Scientific Journal Database (VIP), Chinese Biomedical Literature Database (CBM), and WanFang Data
(WF). The last search for all databases was performed on 31 January 2013. Search strategies
Titles with Rhodiola, mono-preparations of Rhodiola formulation and heart disease were searched, abstract and mesh terms in English or Chinese using the following search terms: Rhodiola, “Hongjingtian”(Chinese name of Rhodiola), “Nuodikang capsule”, “Dazhuhongjingtian capsule” , “Dazhuhongjingtian injection”, “coronary
Page 2 of 29
heart disease”, “Angina pectoris”, “ischemic heart disease”, “guanxinbing” (Chinese pinyin), “xinjiaotong”(Chinese pinyin) were searched. The strategy for searching
ip t
PubMed and other English databases is outlined below: Inclusion and exclusion criteria
cr
Inclusion criteria: Only randomized controlled trials (RCTs) in English or Chinese
us
were included regardless of being published or unpublished. The term “Rhodiola formulation” was defined as a formulation that contained only Rhodiola plant
an
regardless of which species it was derived from. The term “RWM” was defined as western medicines based on the Chinese clinical guidelines for the diagnosis and
M
treatment of cardiovascular diseases, including nitrate esters, statins, platelet inhibitors, β-receptor blockers and calcium channel blockers. Improvement in
te
d
symptoms was defined as at least 50% basic symptomatic improvement and 80% significant symptomatic improvement as assessed by reduction in frequency with
Ac ce p
which angina chest pain was felt. Improvement in ECG was considered achieved if at least 1mv elevation at ST segment (basic ECG improvement) was observed and nearly normal ECG during an exercise test (significant ECG improvement) was
observed as suggested in ACC/AHA guidelines8. Specific inclusion criteria were: (1) RCTs with or without blinding; (2) Rhodiola formulation medicine as a sole agent or
in combination with other drug regimens compared to other Chinese formulations or other drugs for treating IHD; (3) the formulation had to be produced by a pharmaceutical factory and in accordance with the guidelines of the State Food and Drug Administration of the People’s Republic of China; (4) the diagnoses of IHD
Page 3 of 29
were based on standardized diagnostic criteria, such as Nomenclature and Criteria for Diagnosis of Ischemic Heart Disease/World Health Organization (WHO)2, Coronary heart disease inclusion criteria9, Guiding Principle of Clinical Research on New Drugs
ip t
of Traditional Chinese Medicine10 or other diagnostic criteria for IHD11,12.
cr
Exclusion criteria: (1) the study involved only animal studies or in vitro studies;
us
(2) the diagnostic criteria for angina pectoris were not specified; (3) the report represented duplicate publications of other studies; (4) the dosage of the Rhodiola
an
formulation was not clearly reported. Data extraction
M
Data, such as the details of study design, quality of the study, number of participants, sample size, age, disease period, intervention, outcomes and adverse
te
d
events were independently extracted by two reviewers (Yu L and Liu YQ) using inclusion criteria. Disagreements were resolved by discussion between the two
Ac ce p
reviewers and by seeking the opinion of the third author (Xiong HY) when necessary. Quality assessment
The quality of methodology used in all the studies that were included in this
review was independently evaluated by two reviewers (Yu L and Liu YQ) using the Cochrane Collaboration′s tool13. Seven criteria were applied: (1) random sequence
generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting and (7) other bias (defined as baseline data comparability). For each domain, the evaluation was denoted as low risk, high risk or unclear risk according to the
Page 4 of 29
descriptions of the method in each study. Any disagreement was resolved by discussion with the third author (Xiong HY).
ip t
Data analysis First, all key data of each included study were summarized in a table. Second, data
cr
analysis was performed with Review Manager (Revman) version 5.1 software. Effect
us
sizes were presented by odds ratio (OR) and 95% confidence intervals (CIs). Meta-analysis was used if the included trials had acceptable homogeneity of study
an
design, participants, interventions, controls and outcome measures. Overall analysis and subgroup analysis employed random-effects model because clinical heterogeneity
M
of the trials could not be guaranteed. Statistical heterogeneity across studies was evaluated by the Cochran’s Chi-squared (χ2) test (with P
S0965-2299(14)00065-X http://dx.doi.org/doi:10.1016/j.ctim.2014.05.001 YCTIM 1339
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
22-4-2013 23-4-2014 3-5-2014
Please cite this article as: Yu L, Qin Y, Wang Q, Zhang L, Liu Y, Wang T, Huang L, Wu L, Xiong H, The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: A systematic review and metaanalysis of randomized controlled trials, Complementary Therapies in Medicine (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Introduction: Ischemic heart disease (IHD), which is synonymous with the term “coronary heart
ip t
disease”, is the leading cause of death in the world1. It is defined as myocardial impairment due to an imbalance of coronary blood flow and myocardial impairment
cr
caused by changes in the coronary circulation. IHD can be classified into different
us
categories: Primary cardiac arrest, Angina pectoris, Myocardial infarction, Heart failure in IHD and Arrhythmias. Angina pectoris is the main clinical symptom seen in
an
IHD patients, and it is characterized by discomfort in the chest, jaw, should, or arm2-3. The most common treatment of IHD uses western medicines, mainly nitrate esters,
M
statins and platelet inhibitors. It is thought that though western medicines have rapid onset and are effective and reliable, their long-term use is associated with side effects
te
d
and risk of developing drug resistance due to long-term use. Compared with western medicine, traditional Chinese medicines used for treating IHD have low toxicity
Ac ce p
and fewer side effects.
Rhodiola (Crassulaceae) is a famous genus of medicinal herbs in China. In
traditional Chinese medicine, Rhodiola species have been used as a tonic, hemostatic, or antibechic agent for treatment of leucorrhea, contusion, cold/flu-like symptoms and maintain healthy cardiovascular function4. Phytochemical studies have revealed that
the main bioactive compounds, salidroside (SAL) and tyrosol (TYR) are similar to those used in modern medicine for improving cardiovascular function. These compounds exert pharmacological effects, such as enhancing myocardial contractility, increasing myocardial contraction and inducing hypotension in laboratory animals5-7.
Page 1 of 29
Based on the traditional Chinese medicine theory and the cardioprotective effects of
pharmacology,
Rhodiola
formulations
such
as
Nuodikang
capsule,
ip t
Dazhuhongjingtian injection, Dazhuhongjingtian capsule and other Rhodiola medicines have been used for a long time to treat IHD, and many clinical studies
cr
published in Chinese language have claimed that Rhodiola formulation can relieve the
us
symptoms of IHD. However, there has been no systematic review to assess the effects and safety of Rhodiola formulations. The aims of this systematic review were to
an
summarize and critically evaluate the effects of different Rhodiola formulations on treating IHD, both as a sole agent and in combination with other drug regimens.
M
Methods Sources of information
te
d
Clinical trials were searched and retrieved from major electronic databases including: PubMed, Science Direct, the Cochrane Library, China National Knowledge
Ac ce p
Infrastructure (CNKI), China Master Theses Full-text Database (CMTD), China Doctor Dissertations Full-text Database (CDMD), Chinese Scientific Journal Database (VIP), Chinese Biomedical Literature Database (CBM), and WanFang Data
(WF). The last search for all databases was performed on 31 January 2013. Search strategies
Titles with Rhodiola, mono-preparations of Rhodiola formulation and heart disease were searched, abstract and mesh terms in English or Chinese using the following search terms: Rhodiola, “Hongjingtian”(Chinese name of Rhodiola), “Nuodikang capsule”, “Dazhuhongjingtian capsule” , “Dazhuhongjingtian injection”, “coronary
Page 2 of 29
heart disease”, “Angina pectoris”, “ischemic heart disease”, “guanxinbing” (Chinese pinyin), “xinjiaotong”(Chinese pinyin) were searched. The strategy for searching
ip t
PubMed and other English databases is outlined below: Inclusion and exclusion criteria
cr
Inclusion criteria: Only randomized controlled trials (RCTs) in English or Chinese
us
were included regardless of being published or unpublished. The term “Rhodiola formulation” was defined as a formulation that contained only Rhodiola plant
an
regardless of which species it was derived from. The term “RWM” was defined as western medicines based on the Chinese clinical guidelines for the diagnosis and
M
treatment of cardiovascular diseases, including nitrate esters, statins, platelet inhibitors, β-receptor blockers and calcium channel blockers. Improvement in
te
d
symptoms was defined as at least 50% basic symptomatic improvement and 80% significant symptomatic improvement as assessed by reduction in frequency with
Ac ce p
which angina chest pain was felt. Improvement in ECG was considered achieved if at least 1mv elevation at ST segment (basic ECG improvement) was observed and nearly normal ECG during an exercise test (significant ECG improvement) was
observed as suggested in ACC/AHA guidelines8. Specific inclusion criteria were: (1) RCTs with or without blinding; (2) Rhodiola formulation medicine as a sole agent or
in combination with other drug regimens compared to other Chinese formulations or other drugs for treating IHD; (3) the formulation had to be produced by a pharmaceutical factory and in accordance with the guidelines of the State Food and Drug Administration of the People’s Republic of China; (4) the diagnoses of IHD
Page 3 of 29
were based on standardized diagnostic criteria, such as Nomenclature and Criteria for Diagnosis of Ischemic Heart Disease/World Health Organization (WHO)2, Coronary heart disease inclusion criteria9, Guiding Principle of Clinical Research on New Drugs
ip t
of Traditional Chinese Medicine10 or other diagnostic criteria for IHD11,12.
cr
Exclusion criteria: (1) the study involved only animal studies or in vitro studies;
us
(2) the diagnostic criteria for angina pectoris were not specified; (3) the report represented duplicate publications of other studies; (4) the dosage of the Rhodiola
an
formulation was not clearly reported. Data extraction
M
Data, such as the details of study design, quality of the study, number of participants, sample size, age, disease period, intervention, outcomes and adverse
te
d
events were independently extracted by two reviewers (Yu L and Liu YQ) using inclusion criteria. Disagreements were resolved by discussion between the two
Ac ce p
reviewers and by seeking the opinion of the third author (Xiong HY) when necessary. Quality assessment
The quality of methodology used in all the studies that were included in this
review was independently evaluated by two reviewers (Yu L and Liu YQ) using the Cochrane Collaboration′s tool13. Seven criteria were applied: (1) random sequence
generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting and (7) other bias (defined as baseline data comparability). For each domain, the evaluation was denoted as low risk, high risk or unclear risk according to the
Page 4 of 29
descriptions of the method in each study. Any disagreement was resolved by discussion with the third author (Xiong HY).
ip t
Data analysis First, all key data of each included study were summarized in a table. Second, data
cr
analysis was performed with Review Manager (Revman) version 5.1 software. Effect
us
sizes were presented by odds ratio (OR) and 95% confidence intervals (CIs). Meta-analysis was used if the included trials had acceptable homogeneity of study
an
design, participants, interventions, controls and outcome measures. Overall analysis and subgroup analysis employed random-effects model because clinical heterogeneity
M
of the trials could not be guaranteed. Statistical heterogeneity across studies was evaluated by the Cochran’s Chi-squared (χ2) test (with P
