Effectiveness and safety of traditional Chinese medicine on stable chronic obstructive pulmonary disease: A systematic review and meta-analysis

23 (2015) 603–611

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Complementary Therapies in Medicine journal homepage: www.elsevierhealth.com/journals/ctim

Review

Effectiveness and safety of traditional Chinese medicine on stable chronic obstructive pulmonary disease: A systematic review and meta-analysis Wang Haifeng a,b,1 , Zhang Hailong a,b,1 , Li Jiansheng b,c,∗ , Yu Xueqing a,b , Li Suyun a,b , Li Bin a,b , Xie Yang a,b , Bai Yunping b,c a

Department of Respiratory Medicine, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment & Chinese Medicine Development of Henan Province, Zhengzhou 450046, China c The Geriatric Department of Henan University of TCM, Zhengzhou 450046, China b

a r t i c l e

i n f o

Article history: Received 4 November 2014 Received in revised form 27 January 2015 Accepted 15 June 2015 Available online 27 June 2015 Keywords: Traditional Chinese medicine Chronic obstructive pulmonary disease randomized controlled trials systematic review

a b s t r a c t Objective: This study was intended to evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) on stable chronic obstructive pulmonary disease (COPD). Method: A systematic review was conducted of clinical trials that compared TCM plus conventional medicine treatment versus conventional medicine treatment alone. Randomized controlled trials (RCTs) of clinical therapeutic studies on COPD by TCM were included. Searches were applied to the following electronic databases: The PubMed the Cochrane Library CNKI CBM and VIP. No blinding and language restriction was used. All trials included were analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.2 software was used for data analysis. Result: 37 randomized clinical trials enrolling 3212 patients were included. Follow-up duration ranged from 4 weeks to 1.5 years. Compared to conventional medicine treatment alone, TCM plus conventional medicine treatment showed improvement in forced expiratory volume in one second (FEV1 ) (MD 0.12 L; 95% CI 0.08 to 0.16), and less exacerbation (OR −0.86; 95% CI −1.13 to −0.60). TCM treatment also led to a statistically improvement in SGRQ score compared to placebo (MD −4.36; 95% CI −7.12 to −1.59). There was statistically significant difference in six-minute walk distance (MD 36.66 meters, 95% CI 24.57 to 48.74) found with TCM compared to placebo. Conclusion: Among patients with stable COPD, TCM plus conventional medical treatment therapy might be associated with reduction risk of exacerbation, improvement of lung function, better quality of life and higher exercise capacity. The results were limited by the methodological flaws of the studies. High quality studies are needed to provide clear evidence for the future use of TCM. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 2.1. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 2.3. Studies selection and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 3.1. Study identification and characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605

∗ Corresponding author at: Institute: Henan University of Traditional Chinese Medicine, Adress: No.1 Jinshui Road Zhengzhou, Henan, China. Fax: +86 371 65680028. E-mail address: li [email protected] (L. Jiansheng). 1 These two authors contribute equally to this work. http://dx.doi.org/10.1016/j.ctim.2015.06.015 0965-2299/© 2015 Elsevier Ltd. All rights reserved.

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3.2. 3.3. 3.4.

4. 5.

Quality of the selected articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 Primary Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.4.1. Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.5. Secondary outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.5.1. Lung function: forced expiratory volume in one second (FEV1 ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.5.2. Quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.5.3. Exercise capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606 3.5.4. Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608 3.5.5. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610

1. Introduction Chronic obstructive pulmonary disease (COPD) continues to be an important cause of morbidity, mortality, and health-care costs worldwide.1,2 Disability from the disease is substantial, and is expected to increase in the United States and worldwide.1 Despite these trends, efforts to treat COPD have been disappointing. The only medical therapies that clearly reduce disease progression and mortality are smoking cessation and supplemental oxygen.3,4 Because currently available treatments have minimal impact on disease progression, a strategy to prevent the development of COPD is a critical priority. In China, many traditional Chinese medicines (TCM) modalities are regularly used in COPD patients. Several clinical trials5–7 have shown that TCM might have therapeutic effect for COPD patients including improvement of symptoms, quantity of life and lung function. However, the quality of these trials has not been assessed systematically, Furthermore, A systematic review will be beneficial for current practice and directive for continuing research for new treatment regimens. The objective of this review was to assess positive effects of TCM plus conventional medicine treatment versus conventional medicine treatment in stable COPD in adults. 2. Materials and methods 2.1. Eligibility criteria Administration of TCM for the treatment of stable COPD was acceptable for inclusion, the control group use conventional treatment, all studies were open publication and raw data were provided; Outcomes selected those the most affect COPD process, such as exacerbation, pulmonary function, the six-minute walk test, dyspnea and quality of life (QOL). JADAD score was used to evaluate the quality of all studies, only JADAD Score equal or greater than 4 were selected for systematic review. However, we excluded pharmacokinetic studies, nonrandomized evaluations, and animal/laboratory studies, pulmonary rehabilitation studies, acupuncture studies, external application treatment, catgut implantation at acupuncture point, TCM enema and cupping glass treatment. 2.2. Search strategy We undertook a systematic review of the published work without language restrictions according to the Meta-analysis of observational studies in epidemiology (MOOSE) guidelines.8 Two reviewers (YXQ and LSY) do thorough literature search, they identified relevant randomized controlled trials independently from

1966 to December 2012, by a systematic search of PubMed, EMBASE, AMED, Chinese BioMedical Literature Database, and the Cochrane Library. Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), China science and technology journal database (VIP) and Wanfang Data, with the following terms: (Chronic obstructive pulmonary disease OR COPD OR chronic obstructive lung disease OR chronic obstructive airway disease OR chronic obstructive respiratory disease OR chronic bronchitis OR chronic emphysema) AND (Chinese medicine OR traditional Chinese medicine OR Chinese herbal medicine OR Chinese herbal drug OR traditional herbal medicine OR herbal medicine). 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-analysis, to ensure a thorough search. 2.3. Studies selection and data extraction Two reviewers (LB and XY) 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, and study design and therapy duration. Reviewing study design included following criteria: methods of sequence generation, allocation concealment, and complete description of those who were blinded,9 use of intention-to-treat analysis and whether the trial was stopped prior to the planned duration, all methodological features capable of impacting effect sizes. Any disagreements were resolved by discussion with a third author (B. Y. P.) to reach a consensus. The primary outcome measures were exacerbation. The secondary outcome measures included pulmonary function, the six-minute walk test, dyspnea, QOL and adverse events. The data was entered into an electronic database by the two reviewers separately, avoiding duplicate entries existed; 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. 2.4. Data analysis The statistical package (Rev Man 5.2) provided by the Cochrane Collaboration was used to analyze the data. We also applied a random-effects model as part of sensitivity analysis. Dichotomous

W. Haifeng et al. / 23 (2015) 603–611

CNKI

WanFang

VIP

CBM

Pubmed

605

Embase

Cochrane

574 potentially relevant citations identified 552 searched from electronic database 22 additional eligible articles provided

by hand search 290 citations excluded on the basis of titles and abstracts 284 studies included after read the titles and abstracts 4 repeated 4 not available in full text 276 full-text articles retrieved for detailed evaluation

132 articles excluded 6 animal experiment 22 not COPD clinical trial 2 not pure Chinese medicine 3 Nursing Research 15 Mechanism research 26 COPD exacerbation 3 Without suitable data 36 Without proper outcome 2 external therapy 3 without diagnostic criteria 3 compared with other Chinese

144 articles included for read the full-text articles

medicine 1 Complicated intervention 3 review articles 1 combine with cor pulmonale 1 combine with lung rehabilitation treatment 2 acupuncture treatment 3 Chinese patent drug

107 articles excluded 37 articles included in the Meta-analysis 2 English 35Chinese Fig. 1. The quality of reporting of meta-analyses flow diagram for the meta-analysis. * Graded each RCT using the modified Jadad scale, scores of 0–3.5 represent poor or low quality were excluded.

data was presented as Odd Ratio (OR), with 95% confidence intervals (CI). Continuous outcomes were presented as weighted mean difference, with 95% CI Analyses were performed by intentionto-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. 3. Results 3.1. Study identification and characteristics An initial search identified 574 potentially relevant articles, a total of 290 articles were excluded after reading title and abstract. In the identified 284 potentially eligible reports, 4 articles were

excluded because of duplicated, 4 were excluded because of without full text, 132 articles were excluded for further assessment. The most frequent reasons for exclusion were other type of intervention examined, either no clinical outcomes reported, or not a randomized trial. A total of 144 studies were included into the review. Fig. 1 summarized the search results based on the quality of reporting of Meta-analyses flow diagram. The bibliographic details of these trials are given in Fig. 1. The studies included 3212 participants, of whom 1698 were randomized to TCM treatment and 1514 to conventional group. The size of the studies varied greatly, the largest study with 306 participants,7 and the smallest study only had 38 participants.10 The age of patients in the included studies ranged from 37 to 85 years old. Most trials included more males (54–89%) than female’s participants and a similar gender distribution in both treatment groups. The exception was a few studies with relatively more women, or with more uneven gender distribution between the treatment groups. Disease severity in the included studies ranged from mild to severe COPD. In a majority of the studies the patients had a mean baseline lung function of less than 50% FEV1 predicted

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Fig. 2. Comparison of TCM + conventional treatment versus conventional treatment, exacerbations.

indicating that a large proportion of participants had severe COPD. The baseline lung function was generally well balanced between the treatment groups. The included studies had similar inclusion and exclusion criteria. Patients of either sex, with a clinical diagnosis of stable COPD, were eligible for study entry if they were aged over 40 years and had a smoking history of at least 10 pack-years. Participants were excluded if they had a significant disease other than COPD usually including other significant respiratory conditions such as asthma or a respiratory infection in the weeks before enrolment. All studies used TCM and conventional treatment daily. All of the included studies were randomized, placebocontrolled, and of parallel group design. The total duration of treatment varied from 1 month to 18 months. All included trials were designed to compare TCM plus conventional treatment with the conventional treatment alone. 3.2. Quality of the selected articles The quality assessment of included trials is shown in Table 1. Trial quality was variable. All trials were double blinded (researchers and subjects). Allocation concealment was adequate in 4 RCTs,7,11–13 and unclear in the remaining 36 RCTs. Information on withdrawal rates was available for 8 trial.7,11,13–18 Reporting of loss to follow-up was variable and only available for 5 RCTs,7,11,15,18,19 and ranged from 1.54%11 to 10.2%7 . 3.3. Publication bias Although we conducted comprehensive searches and tried to avoid bias, most trials were published in Chinese, 2 trials were published in English,7 and 38 studies were performed in china. We could not exclude potential publication bias.

statistically significant when analyzed using a fixed-effect model (OR −0.86; 95% CI −1.13 to −0.60) Figs. 2 and 3. 3.5. Secondary outcomes 3.5.1. Lung function: forced expiratory volume in one second (FEV1 ) 16 trials (1747 patients) used FEV1 as the outcome,7,10–14,18,21,23,28–34 the pooled analysis showed a statistically significant improvement in through FEV1 with TCM plus conventional treatment compared to conventional treatment alone (MD 0.12 L; 95% CI 0.08 to 0.16). Although there was moderate heterogeneity among the studies (I2 = 58%), the result was similar when analyzed using a random-effects model (MD 0.14 L; 95% CI 0.07 to 0.21) Fig. 4. 3.5.2. Quality of life Many of the included studies measured health-related quality of life using the St. George respiratory questionnaire (SGRQ). 12 studies involving 1020 participants used the SGRQ,13,14,17,19,22,25,30,35–39 a decrease in SGRQ score denotes an improvement in quality of life and a difference of at least four units is regarded as clinically significant. TCM treatment led to a statistically significant improvement in health-related quality of life compared to placebo (MD −4.36; 95% CI −7.12 to −1.59) Fig. 5. 3.5.3. Exercise capacity There was significant heterogeneity in change in six-minute walk distance between the 12 medium-term studies that measured

3.4. Primary Outcomes 3.4.1. Exacerbations 12 studies reported COPD exacerbations as a specific outcome or as part of the safety data (1201 participants).7,10,11,16,20–27 The definition of COPD exacerbation was similar among the studies; exacerbations were defined as an acute events characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. The total duration of treatment varied from 6 month to 18 months. All of the studies reported the number of participants with one or more exacerbation in each treatment group. There were fewer participants suffering one or more exacerbations in the TCM group than in the placebo group. The difference between the groups was

Fig. 3. Comparison of TCM +conventional treatment versus conventional treatment, funnel plot of exacerbations.

Table 1 Study characteristics and quality. Studies (author)

Year

LI Su-yun7 HONG Min-li10 ZHANG Hai-long11 LI Su-yun12 WU Lei13

2011 2005 2010 2006 2011

14

HE Wen-ju

2010

LI Cheng-hui15 JIAN Xiao-yun16

2010 2012

GAO Xiu-ling17

2012

18

2009 2009

HE Ying-chun20 CHEN Yun-feng21 LIU Jian-yong22

2010 2007 2012

LIU Hui23 MA Li-fen24

2008 2011

YOU Bo-wen25

2008

26

GAO Feng

2012

TANG Cui-ying27 CHEN Xue-mei28 FU Min29 KE Xiao-xia30 ZHANG Hong-chun31 ZHANG Wei32 LI Xue33

2009 2005 2012 2010 2003 2008 2008

ZHU Ting-chang34

2010

FENG Ji-hong35 HE Chang-sheng36 LUO Sheng37

2009 2008 2007

TANG Jie38

2010

ZHENG Shuo-feng39

2010

CHEN Gong-can40 ZHENG Min-yu41 LIANG Ai-ling42

2012 2010 2009

QI Wei-ping43

2009

ZHANG Xiao-yi44 ZHAO Hai-fang45

2008 2010

Number (T/C)

Type of assessable outcomes

Jadad scoresa

7.5 6 5 8 8

Control

Western standard treatment + prescription of TCM therapy Yufeining pill Western standard treatment + prescription of TCM therapy Bufeiyishen granule Jianpi Yifei II(granules of strengthening the spleen and improving the lung) Western medicine treatment Programs and Reinforce lung and kidney Prescription The Chinese medicine of TiaobuFeishen Conventional Atrovent Metered Dose Inhaler (MDI) and Pingchuan Capsules Ventolin inhalant and oral aminophylline + Chinese medicine of Feitong mixture Yupingfeng San Atrovent metered dose inhaling and Mucosolvan + the Chinese medicine of Bufei Yishen fluid Buzhongyiqi oral Granules FeiKangNing capsule tiotropium bromide powder inhalation and oral aminophylline sustained release tablets + Gubentiaofei prescription with traditional Chinese edicine Manzhi Kechuan Ling Western standard treatment and take the Chinese medicine which have the efficacy of open the meridians and Benefit the lung small dose Aminophylline Sustained-release Tablets and inhaling Salbutamol or becotide + Yifei Mixture inhaled bronchodilator therapy + Bufei Huoxue Huatan Chinese medicine therapy Routine treatment and bailing capsule Western standard treatment + prescription of TCM therapy Bufei Granule Chinese medicine therapeutie Tiaobufeishen capsules Western standard treatment and Fuzhenghuayu Capsule Traditional Chinese medieine with oral inhalation treatment seretide Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation + Traditional Chinese medicine Bufei Granule The Chinese medicine of BushenJianpi QuyuHuatan decoction The compound prescriptions of reinforcing earth to strengthen metal and Western standard treatment Basic treatment + the Chinese medicine of JianpiYishen decoction TCM syndrome differentiation and placebo of western medicine treatment “Buzhong Yiqi Decoction”combined routine treatment Chinese medicine Fluticasone + propionate theophylline + spleen-transporting kidney-boosting lung-supplementing decoction Quit smoking and was treated by oral theophylline controlled release capsule + supplementing Qi to invigorate spleen herbs The Chinese medicine of LiuJunZi Pill Based on western medicine treatment + mission lung expectorant tong luo herbal medicinal

Western standard treatment Not receive any medication Western standard treatment Placebo Placebo

155/151 20/18 96/99 31/31 108/46

FEV1 FEV1 FEV1 FEV1 FEV1

Western medicine treatment Programs

22/23

FEV1 SGRQ

6

not receive any medication Only with MDI

22/19 33/34

6MWD exacerbations

6 5

Ventolin inhalant and oral aminophylline

53/54

SGRQ 6MWD

4

not receive any medication Atrovent metered dose inhaling and Mucosolvan

33/32 32/32

FEV1 SGRQ

6 6.5

placebo Western standard treatment tiotropium bromide powder inhalation and oral aminophylline sustained release tablets

49/49 59/58 28/28

exacerbations FEV1 exacerbations exacerbations SGRQ

5 4 6

not receive any medication Western standard treatment

40/36 24/24

FEV1 exacerbations exacerbations

4 4

small dose Aminophylline Sustained-release tablets and inhaling Salbutamol or becotide inhaled bronchodilator therapy

30/30

exacerbations SGRQ

5

30/30

exacerbations

4

Western standard treatment Western standard treatment placebo Placebo Gubenkechuan tablets Western standard treatment simple application of the treatment seretide

30/30 91/90 67/61 103/44 30/30 30/32 30/30

Exacerbations FEV1 FEV1 FEV1 SGRQ 6MWD FEV1 FEV1 FEV1

4 7.5 7 7 6 4 5

Salmeterol Xinafoate and fluticasone propionate powder for inhalation Placebo Western standard treatment Western standard treatment

26/27

FEV1

6

30/30 30/30 28/29

SGRQ SGRQ SGRQ

5 5 5

Western standard treatment

34/35

SGRQ

4

Western standard and placebo of Chinese medicine treatment

36/36

SGRQ

7

Western standard treatment Nucleotide and casein oral solution Fluticasone + propionate Theophylline

40/40 96/48 30/30

6MWD 6MWD 6MWD

4 4 4

Quit smoking and was treated by oral theophylline controlled release capsule Not receive any medication Western standard treatment

24/23

6MWD

6

38/35 40/40

6MWD 6MWD

4 4

Abbreviations: T/C, treatment group/control group; FEV1 , Forced expiratory volume in one second; 6MWD, six minute walking distance; SGRQ, St. George respiratory questionnaire. a Modified Jadad scale was use.

exacerbations 6MWD exacerbations exacerbations 6MWD SGRQ 6MWD

607

Treatment

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MA Yan-tao ZHU Li-fen19

Chemotherapy regimen

608

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Fig. 4. Comparison of TCM + conventional treatment versus conventional treatment, FEV1.

this outcome.7,11,13,15,17,30,40–45 When these data were pooled, there was statistically significant difference found with TCM compared to placebo (MD 36.66 meters, 95% CI 24.57 to 48.74) Fig. 6. 3.5.4. Adverse events An adverse drug event was any unexpected or dangerous reaction to a drug. An unwanted effect was caused by the administration of a drug. The onset of the adverse reaction may be sudden or

develop over time. No obvious adverse events occurred in 40 trials. Eight trials 7,11,13,19,30,34,42,44 reported adverse events. These included throat discomfort, dry mouth, palpitation, allergic reaction, anorexia, diarrhea and abdominal distension. Most of the adverse events were not severe. They disappeared without special treatment. The adverse events in the TCM treatment group were higher than those in the control group; there was no statistically significant difference between the two groups. Although the

Fig. 5. Comparison of TCM + conventional treatment versus conventional treatment, SGRQ score.

Fig. 6. Comparison of six-minute walk distance in TCM + conventional treatment versus conventional treatment.

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authors did not find any related information about adverse effects recorded, potential or long-term adverse effects in the included trials could not be excluded. 3.5.5. Mortality No studies reported the number of deaths during the treatment period in each treatment group, and no study take mortality as a specified outcome. So we could not draw any definite conclusion about TCM on mortality. 4. Discussion For a long period of time, smoking cessation was the only treatment affecting the progression of COPD in the sense that it was shown to reduce the rate of decline of FEV1 and mortality.46,47 Pharmacotherapy for COPD, however, has improved substantially in the last decade. The availability of inhalational corticosteroids,48 fixed combinations of inhaled cortisteroids and LABAs,49 and long-acting anticholinergic or muscarinic antagonists (LAMAs)50 has allowed improved outcomes in these patients substantially more than was possible before. In recent years, new data on TCM therapy of COPD became available that shed new light on this question.5,7 This review of randomized trials shows the current evidence in TCM for COPD. TCM plus conventional medicine treatment was associated with a reduction in the risk of exacerbations in comparison and an improvement in COPD patients’ QOL with the treatment of conventional medicine alone. Furthermore, TCM also lead to an improvement in FEV1 . These results were positively encouraging and promising of combining TCM with conventional treatment, which might be beneficial to lung function. TCM also lead to better exercise ability. The reduction in the risk of COPD exacerbations with TCM therapy reported here is consistent with the results of previous report.7 Our analysis demonstrated long-term (>6 months) exacerbations benefit with TCM therapy. As we know, COPD exacerbations usually associated with high morbidity and mortality and pulmonary function reduction. Therefore, control COPD exacerbations now is the main treatment purpose of many trials. We demonstrated a significantly improvement in COPD patients’ quality of life with TCM use. There has been controversy in the literature regarding the association between TCM use and benificiation. Establishing and quantifying this benificiation is essential, TCM always evaluating patient’s disease by their symptoms, or by the doctors experience, and that difficult to quantified. The included studies in this review measured health-related quality of life using the SGRQ, 12 published randomized trials demonstrated a potential association between TCM use and QOL. Using international questionnaire of COPD in future clinical trials may prevent misclassification bias that could alter true associations of TCM with QOL. The mechanism of the benificiation of TCM therapy on COPD remains unclear. One potential explanation is that TCM therapy may increasing system and local airway immune ability in patients with COPD. This could increase the ability of the innate immune system to defend against primary bacterial infections or post viral super infections. This hypothesis is supported by many recent trial that suggested that TCM use increase lung specific and generalized biomarkers of systemic inflammation in patients with COPD.51–53 The definite biological explanation for this observation remains unclear. Further exploration of the mechanism of TCM therapy and subsequent morbidity and mortality in patients with COPD will be required. Our study has limitations, which mainly stem from the quality of reported data. First, many of these trials were small and shortterm, resulting in few events. As a result of small numbers, the 95% CIs are wide, resulting in some uncertainty as to the precise magni-

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tude of the observed risk. Second, few relevant articles on TCM for COPD have been published in the English medical journals, and the limited evaluation of TCM beyond China reduces its external validity. Third, treatment was applied according to a diagnosis of COPD without further syndrome differentiation according to traditional Chinese methodology. Fourth, the type of conventional medicine used and the dosages were often impropriate reported, so it was not sure that all studies used similar medications. Fifth, a lot of studies did not provide explicit definitions for exacerbation of COPD. There can be a high degree of clinical overlap with COPD exacerbations. Which would influence the conclusion of this review. Sixth, considerable qualitative heterogeneity was present in the populations studied in these clinical trials. Different criteria for age, disease severity (ie, baseline FEV1 ), and smoking status may limit the generalizability of our findings to a particular population. Seventh, here were no trials reported death, so our analysis lack of mortality data from all studies. Adverse effect was reported by Liet al.,7 as only dry mouth and mild drowsiness, the adverse events were not severe. Most of them spontaneously recovered without special treatment. No obvious adverse events occurred in these trials. However, the concrete conclusion regarding safety cannot be determined from this review due to the limited evidence provided by the eligible trials, in order to proper assess the safety of TCM, large-scale clinical trials with long-term follow up are required. 5. Conclusions In conclusion, despite certain limitations, our findings have potential implications. Our findings indicate a reduction in the risk of exacerbations and improvement of lung function, better quality of life and exercise capacity with TCM in patients with COPD. No major adverse effects were reported. Therefore, further thorough investigation, large-scale, proper study design, randomized trials of TCM for COPD 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, blinding of outcome assessors, and use functional outcome as the primary outcome measured at long-term follow-up. Reports of the trials should conform to the recommendations of the CONSORT statement. Conflict of interest The authors declare that they have no conflict of interest. Authors’ contributions This project was initiated and developed by LJS and WHF. LJS and WHF were involved in the design of the study and the interventions of the protocol. WHF and ZHL were involved in drafting and writing the manuscript. YXQ and LSY was involved in evaluating the data. LB, XY and BYP were involved in coordinating the study and supervising the work. All authors read and approved the final manuscripts. Acknowledgments This study was sponsored by the National natural science foundation of China (Grant No. 81102576), Program for Research Project for Practice Development of National TCM Clinical Research Bases (Grant No. JDZX2012028), Program for Science &Technology Innovation Talents in Universities of Henan Province (Grant No.14HASTIT029), Program for Traditional Chinese medicine Science foundation of Henan Province (Grant No. 2014ZY01011),

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Program for Science & Technology Innovation Talents in Henan College of Chinese Medicine (2012XCXRC02), and Program for fundamental scientific research funds support plan in Universities of Henan Province (2014KYYWF-YQ06).

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