Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2018 / Article

Review Article | Open Access

Volume 2018 |Article ID 6207524 | 27 pages | https://doi.org/10.1155/2018/6207524

Effectiveness and Safety of Compound Chinese Medicine plus Routine Western Medicine in In-Stent Restenosis: A Meta-Analysis and Systematic Review

Academic Editor: Kieran Cooley
Received29 Oct 2017
Accepted28 Mar 2018
Published11 Jul 2018

Abstract

Objective. To examine the effects and safety of oral compound Chinese medicine (CCM) plus routine western medicine (RWM) in in-stent restenosis (ISR). Methods. Various electronic databases (CBM, CNKI, VIP, Wanfang, PubMed, EMBASE, and Cochrane Library) were searched until April 2017. The quality of the included studies was evaluated, and meta-analyses were performed using RevMan5.3 and STATA 12.0 software. Moreover, funnel plot and Egger’s publication bias plots were analysed to identify publication bias and adverse reactions were reported. A sensitive analysis was carried out according to the quality score. Results. In all, 40 RCTs involving 4536 patients were selected for this review. The pooled estimates of three studies showed that the benefit to the number of ISRs (NoR) was more substantial for CCM plus RWM than for RWM alone (RR 0.24, 95% CI 0.10 to 0.57, , ). The rate of ISR was significantly lower for CCM plus RWM than for the same RWM alone (RR 0.44, 95% CI 0.37 to 0.53, ; , ). CCM plus RWM benefitted the rate of ISR when a CM placebo plus RWM was used as the control intervention (RR 0.34, 95% CI 0.20 to 0.57, ; , ). The difference of adverse reactions was not significant. For secondary outcomes, the CCM plus RWM group did not reduce the rates of revascularization and cardiac death, but it did reduce the rate of recurrent angina over the results observed in the RWM alone group. In addition, funnel plot and Egger’s publication bias plot indicated that there was publication bias. The association between the use of CCM plus RWM and RWM alone remained significant after the sensitivity analysis excluding studies with low quality score (quality score ⩽ 4) with a pooled RR of 0.41 (95% CI, 0.34–0.50). Conclusion. Oral CCM plus RWM clearly benefitted patients with percutaneous coronary intervention (PCI) because it prevented and treated ISR better than was observed for either RWM alone or a CM placebo plus RWM.

1. Introduction

Currently, percutaneous coronary intervention (PCI) is widely used around the world to treat coronary artery disease (CAD) and has significantly reduced mortality in patients with acute coronary syndromes [1]. However, the incidence rate of in-stent restenosis (ISR) is still approximately 10%, even accounting for the introduction of drug-eluting stents (DES) [2], and reaches as high as 40%–50% in patients with multivessel involvement [3]. ISR therefore inflicts a heavy burden on both the lives of patients with CAD and the economy and remains a challenge to the implantation of PCI and CAD prognoses.

In traditional Chinese medicine (TCM), the typical symptoms of ISR, such as chest pain and chest tightness, are referred to as “Xiongbi” [4]. TCM presents mature theories and is supported by abundant clinical experience for treating “Xiongbi”. In recent years, the efficacy and safety of TCM in ISR has been widely studied with remarkable results. Studies have shown that TCM not only clearly alleviates the typical symptoms of ISR but also improves its long-term prognosis, suggesting that TCM may lead to promising applications for the treatment of ISR.

Previous reviews focused on this issue were published in 2008 [5], 2012 [6], and 2014 [7]. The first two of these studies were systematic reviews (SRs), and the latter was a meta-analysis. They explored the effects of many types of PCI and included studies with small sample sizes (fewer than 30 cases) and that explored a single TCM herb. In addition, a presearch showed that, in the 3 years since 2014, more studies have supported the efficacy and safety of oral compound Chinese medicines (CCMs) in ISR. In this SR, we applied more rigorous inclusion and exclusion criteria and aimed to explore whether oral CCM plus routine western medicine (RWM) is effective and safe for treating ISR after stent implantation. We use CCM because it has wider applications in clinical practice and conforms better to TCM theory.

2. Methods

This SR was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [8] and the Cochrane Handbook [9] Systematic review and is registered at PROSPERO with the registration number CRD42017075368 (https://www.crd.york.ac.uk/PROSPERO).

2.1. Search Strategy

A comprehensive search of 7 medical databases, including the PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), Wanfang, and Chinese Biomedical (CBM) databases, was conducted through April 2017 without a language restriction. We performed the search using individually or combined Mesh terms for all fields relating to the patients (coronary heart disease and coronary artery disease) and interventions (traditional Chinese medicine, Chinese herbal medicine, compound Chinese medicine, Chinese prepared medicine, Chinese herbal formula, and Chinese herbs) of interest. All titles/subjects related to the outcome (in-stent restenosis) were searched. When searching Chinese databases, the above terms were searched in Chinese.

2.2. Inclusion Criteria

Only randomized controlled trials (RCTs) were included. We focused on trials with participants diagnosed with major angiographic criteria-documented [10] CAD who were eligible for stent implantation (with either bare metal stents or drug-eluting stents) regardless of their gender, age, disease course, comorbidity, and ethnic origin. The baseline characteristics of each study were consistent. The interventional treatment was any oral CCM plus RWM administered for at least 1 month regardless of dosage. The control group was treated with the same RWM or with a CM placebo plus the same RWM. “CCM” included Chinese prepared medicines or Chinese herbal formulas. The compositions of the CCM were detailed. Our primary outcomes were restenosis occurring within at least 6 months of follow-up. Coronary in-stent restenosis is classically defined as the angiographic detection of a recurrent stenosis with a diameter greater than 50% at the stent segment or the 5 mm segments adjacent to it (in-segment restenosis). The drop-out rate for coronary angiography (CA) review was required to be lower than 20%. Each included study was required to report the primary outcome. Secondary outcomes could be major adverse cardiac events (MACE), including recurrent angina, myocardial infarction, revascularization, and cardiac death. Only secondary outcomes that improved in equal to or more than 50% of cases were considered responses. In addition, adverse reactions were considered as a primary safety outcome. When there were several follow-up points, only the last one was considered.

2.3. Exclusion Criteria

Studies with a small sample study (less than 30 cases), duplicate reports, and pilot studies were excluded. Any trial that failed to satisfy the inclusion criteria or for which required data were unavailable was excluded.

2.4. Data Extraction

Two reviewers (Jinjin Lu and Yan Li) independently extracted the data using a standardized extraction form. Disagreements were resolved by census or consultation with a third reviewer (Wenhao Jia). The following items were extracted: study name, year of publication, sample size, details of the trial design (i.e., randomization, allocation concealment, and blinding), eligibility criteria, general characteristics of patients, details of intervention and control therapies, details related to outcomes, details related to drop-outs, and other information that may help detect bias.

2.5. Quality Assessment

Two reviewers (Xiaoyun Cui and Kun Zhou) independently assessed the methodological quality of the included studies using the Cochrane Collaboration’s tool [11], which is a domain-based evaluation tool used to generate a “risk of bias” table for each study. Any disagreement was resolved by consensus or consultation with a third reviewer (Yanchao Huang). The domains used for assessment were sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias (e.g., early termination, contamination, and conflict of interest). Because it is difficult to blind participants in studies of Chinese herbal medicines, performance bias was likely present in all trials. With regard to the objective outcomes adopted in this SR, such as ISR and MACE, performance bias and detection bias might not be as important, and we therefore summarized these trials as low-risk. In addition, with regard to selective outcomes, this domain was ranked as “low-risk” unless the outcomes were critical to our issue.

2.6. Data Analysis

Data synthesis and analysis were performed with RevMan software 5.3 and STATA 12.0 software (StataCorp LP, College Station, TX) [9]. Dichotomous data were measured as relative risk (RR), while continuous data were measured as the mean difference (MD), both with corresponding 95% confidence intervals (CIs). Heterogeneity across trials was measured with the Cochran test and is presented as statistics. Only trials with lower than 85% were used for the meta-analysis, and the characteristics of the included trials were similar. A fixed effect model was used if was lower than 25%. Otherwise, a random effect model was applied under the assumption that any heterogeneity was readily explainable. Furthermore, funnel plot and Egger’s test were performed to detect heterogeneity and publication bias, respectively, if sufficient sources were available. A 2-tailed value less than 0.05 was considered significant. A sensitivity analysis was conducted to assess the stability of the results.

3. Results

3.1. Study Identification

All eligible studies were screened and identified (Figure 1). A total of 2198 records were retrieved. Of these, full-text evaluations were conducted on 114 studies. In all, 74 of these 114 studies were excluded for the following reasons: non-RCT or quasi-RCT ; follow-up < 6 months ; drop-outs from CA review > 20% or failure to report the prespecified primary outcome ; failure to report the composition of the CCM ; control group consisted of a CM injection or another CCM ; review ; treatment duration < 1 month or unclear ; unavailable data ; patients without stent implantation ; small study sample size ; and unclear baseline characteristics . Finally, a total of 40 RCTs with a total of 4536 patients were included in this SR [1251].

3.2. Characteristics of Included RCTs

All studies were conducted in China from 2010 to 2017. The average age of the patients ranged from 52.93 to 69.27 years old. Most trials had more males than females. The diagnostic criteria for CAD were mainly based on CA criteria or the Nomenclature and Diagnostic Criteria for Ischemic Heart Disease (World Health Organization, WHO) [52]. All patients successfully underwent stent implantation. The distributions of baseline characteristics were basically the same in each group. Four trials [25, 26, 36, 49] were double-blinded, and, in three trials, the control group used a CM placebo plus RWM [19, 25, 26]. The remaining trials were designed to compare a CCM plus RWM group to a group treated with same RWM alone. Of the 40 studies, 20 used a decoction, 1 used an oral liquid, 2 used granules, 4 used pills, 12 used capsules, and 1 used tablets. RWM mainly consisted of aspirin, Clopidogrel, angiotensin-converting inhibitor (ACEI)/angiotensin II receptor blocker (ARB), beta-blockers, and statins. The dosage and types of RWM were prescribed according to the recommendations of Chinese Society of Cardiology Guideline [10]. Overall, 33 kinds of CCM were used, and the treatment courses ranged from 3 to 12 months with a follow-up time of 6 to 18 months. For outcomes, ISR was assessed by computed tomography angiography (CTA) or CA in all trials; adverse reactions caused by CCMs were reported in 11 studies but were significant in only 2 studies [26, 38]; MACE were reported in 12 studies and included recurrent angina , myocardial infarction , revascularization , and cardiac death (Tables 1 and 2).


Author,
Year
No. of patients
(EG/CG)
Age, mean
(SD/range), EG/CG, year
Gender, M/F, N.Co-morbidities, N.
EG/CG
Lesion site,
EG/CG
Lesion number,
EG/CG
Stent number,
EG/CG
CAD diagnostic guidelines

DAI GF 2017117 (57/60)63.5 (9.82)
65.07/(8.99)
E: 36/21
C39/21
HTN: 40/41
DM: 33/34
Dyslipidaemia: 49/51
LMCA: 4/3
LAD: 12/13
LCX: 9/10
RAC: 10/11
DBL: 15/16
TBL: 4/5
MBL: 3/2
109/112CA

ZHANG RZ 2017138 (70/68)59.4 (8.5)/57.3 (6.4)E: 41/29
C: 40/28
HTN: 14/13
DM: 10/9
Hyperlipidemia: 12/10
NRNRNR2007: Guideline for Percutaneous Coronary Intervention (CSC)

WANG KL 201662 (32/30)58.93 (5.52)/60.43 (5.39)E: 22/10
C: 16/14
HTN: 25/23
DM: 8/9
Hyperlipidemia: 11/13
NRSBL: 9/8
TBL: 17/15
TBL: 6/8
1.83 ± 0.58/1.98 ± 0.70CA

GONG XY 201692 (46/46)57.8 (1.9)/57.5 (2.1)E: 21/25
C: 20/26
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

TANG YY 201664 (32/32)52.32 (4.12)/53.53 (4.55)E: 20/12
C: 22/10
HTN: 20/19
DM: 19/17
Hyperlipidemia: 25/24
NRNRNRCA

ZHOU JC 201668 (34/34)NRNRNRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

ZHU HB 201664 (32/32)61.5 (5.5)/60.5 (5.8)E: 19/13
C: 18/14
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

XIAO NH 2016120 (60/60)63.15 (9.45)/63.83 (9.50)E: 40/20
C: 39/21
HTN: 44/43
DM: 14/18
NRSBL: 18/19
TBL: 20/19
TBL: 22/22
137/150CA
REN DD 201660 (30/30)55.4 (9.78)/55.76 (9.25)E: 16/14
C: 18/12
HTN: 14/13
DM: 4/5
NRSBL: 16/17
TBL: 10/9
TBL: 4/4
48/47CA

LI QZ 201668 (34/34)60.2 (4.3)/61.3 (5.2)E: 20/14
C: 19/15
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

SUN QY 201688 (44/44)63.1 (3.2)/62.5 (2.6)E: 29/15
C: 28/16
HTN: 19/18
DM: 10/9
Hyperlipidemia: 13/14
NRNRNRCA

XU MT 201672 (36/36)58.2 (4.5)/60.5 (10.5)E: 21/15
C: 20/15
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

MENG XL 201660 (30/30)60 (46~72)/61.5 (49~73)E: 16/14
C: 13/17
HTN: 12/10
DM: 5/5
Arrhythmia: 8/9
NRNRNRInternal medicine

YANG TL 2016343 (172/171)57.93 (9.77)/58.63 (10.27)E: 137/35
C: 134/37
HTN: 105/102
DM: 172/171
LMCA: 6/7
LAD: 117/111
LCX: 101/92
RAC: 77/88
SBL: 66/69
DBL: 86/77
MBL: 23/25
301/298CA

WANG X 2016128 (64/64)65.8 (4.4)/65.3 (4.2)E: 49/15
C: 48/16
NRNRSBL: 26/25
DBL: 23/22
MBL: 16/17
NRPractice of internal medicine
ZHOU W 2015100 (50/50)69.08 (7.46)/69.46 (7.35)E: 28/22
C: 27/23
HTN: 23/24
DM: 9/10
Hyperlipidemia: 20/19
NRNRNR2009: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction and ACC/AHA/SCAI guidelines on percutaneous coronary intervention.

PENG WD 201564 (32/32)61.5 (5.5)/60.5 (5.8)E: 19/13
C: 18/14
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

ZHANG Y 201580 (40/40)53.2 (5.4)/51.9 (5.3)E: 21/19
C: 22/18
NRNRNRNRCA

WANG K 2015148 (75/73)57.6 (10.3)/56.5 (9.1)E: 59/16
C: 56/19
HTN: 32/34
DM: 23/28
Hyperlipidemia: 55/45
NRNRNRCA

LU HW 2014180 (90/90)60.2 (6.9)/61.8 (7.2)E: 48/42
C: 46/44
HTN: 59/53
DM: 23/25
Hyperlipidemia: 13/17
NRSBL: 36/32
DBL: 33/40
TBL: 21/18
132/127Nomenclature and diagnostic criteria of Ischemic heart disease (WHO), 2009: Guideline for Percutaneous Coronary Intervention (CSC)

ZHANG PF 2014123 (61/62)57.44 (8.07)/60.64 (8.91)E: 39/22
C: 38/24
NRNRNRNRCA

SHI QJ 201460 (30/30)60.3 (6.2)/62.8 (6.2)E: 20/10
C: 18/12
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

CHEN K 201480 (40/40)56.2 (5.2)/57.9 (5.3)E: 19/21
C: 20/20
NRNRNRNRCA
LI B 2014102 (51/51)61.2 (5.8)/60.6 (5.8)E: 38/17
C: 36/19
HTN: 22/24
DM: 10/11
Hyperlipidemia: 30/25
NRNR77/81CA

LI CW 201483 (43/40)53.14 (9.45)/54.19 (10.7)E: 27/16
C: 22/18
NRNRNRNR2007: Guideline for Percutaneous Coronary Intervention (CSC)

WANG ZQ 2013100 (50/50)56.92 (12.21)/58.90 (13.19)E:28/22
C:27/23
HTN: 14/16
DM: 8/9
Hyperlipidemia: 12/11
NRSBL: 12/10NRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

ZHANG Q 20131123 (509/514)55.6 ± 7.9/55.5 ± 7.8E: 438/71
C: 441/73
HTN: 274/29
DM: 139/127
Stroke: 3/26
NRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

DENG XD 201362 (31/30)59.0 (42~76)/59.5 (41~78)E: 21/10
C: 20/10
NRLAD: 20/18
LCX: 2/1
RAC: 9/11
NRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

CHEN K 201360 (30/30)55.2 (5.2)/54.9 (5.3)E: 16/14
C: 15/15
NRNRNRNRCA

SI XC 2013120 (60/60)NRNRNRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

HAN P 2012102 (54/48)NRNRNRNRNRNRCA

REN XY 201268 (35/33)56.2 (5.3)/55.9 (5.8)E: 18/17
C: 17/16
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

NIU XY 201271 (41/30)60.5 (6.50)/61.8 (6.1)E: 25/16
C: 18/12
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

GAO XX 201260 (30/30)56.5 (5.3)/55.9 (5.8)E: 16/14
C: 15/15
HTN: 9/11
DM: 11/10
NRNRNRCA
DAI GF 201161 (31/30)61.3 (7.23)/63.5 (6.1)E: 19/12
C: 17/13
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO) 1979

MEI CL 2011124 (61/63)56.3 (5.6)/58.3 (6.1)E: 35/26
C: 36/27
DM: 16/17
HTN: 20/23
NRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

WANG XD 2010132 (68/64)65.2 (9.9)/65.1 (10.4)T: 43/25
C: 45/19
HTN: 59/61
DM: 68/64
Hyperlipidemia: 52/49
LAD: 36/34
LCX: 33/26
RAC: 26/28
SBL: 32/26
DBL: 34/35
TBL: 2/3
131/126CA

CHENG SJ 201060 (30/30)57.9 (5.2)/58.1 (3.9)T: 20/10
C: 22/8
HTN: 16/13
DM: 6/9
hyperlipidemia: 12/11
NRSBL: 19/23
MBL: 11/7
NRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

DAI GF 201094 (49/45)61.2 (6.3)/63.8 (5.9)T: 38/21
C: 26/20
NRNRNRNRNomenclature and diagnostic criteria of Ischemic heart disease (WHO)

LIU LL 201060 (30/30)63.57 (50~75)/62.8 (50~68)T: 19/11
C: 18/12
HTN: 22/19
DM: 12/14
Hyperlipidemia: 5/6
NRNRNR2007: Guideline for Percutaneous Coronary Intervention (CSC)

EG = experimental group; CG = control group; SD = standard deviation; M/F = male/female; N = number of subjects; CAD = coronary artery disease; HTN = hypertension; DM = diabetes mellitus; LMCA = left main coronary artery; LAD = left anterior descending coronary; LCX = left circumflex; RAC = right coronary artery; DBL = double branch Lesions; TBL = three branch Lesions; MBL = multiple branch lesions; CA = coronary angiography; NR = not reported; CSC = Chinese Society of Cardiology; WHO = World Health Organization; SBL: Single branch Lesion; ACC = American College of Cardiology; AHA = American Heart Association; SCAI, Society for Cardiovascular Angiography and Interventions.

Author,
year
InterventionTreatment course (mos)Follow-up (mos)outcomes
CGEG

DAI GF
2017
RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Tongmai decoction P.O. 100 ml bid66ISR,
Response rate of ECG

ZHANG
RZ 2017
RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Huoxue Tongluo capsule P.O. 4 pills tid66ISR,
Response rate of ECG

WANG KL 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Metoprolol tartrate P.O. 12.5 mg bid, Atorvastatin P.O. 10 mg qd.
RWM plus Huxinkang tablets P.O. 10 pills tid66ISR,
Response rate of ECG

GONG XY 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 100 mg qd.RWM plus Huoxue tongmai decoction P.O. 150 ml bid66ISR

TANG YY 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd.RWM plus Yiqi tongluo huatan decoction P.O. 1 dose bid66ISR

ZHOU JC 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Qiwei sanxiong decoction P.O. 1/2 dose bid66ISR

ZHU HB
2016
RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.5 g qd,
Metoprolol tartrate P.O. 75 mg qd, Atorvastatin P.O. 10 mg qd.
RWM plus Mailuotong capsule P.O. 0.84 g tid.66ISR,
Response rate of ECG

XIAO
NH 2016
RWM:Aspirin, Clopidogrel, ACEI/ARB, Beta blocker,
Rosuvastatin P.O. 10 mg qd,
RWM plus Xinxuetong capsule P.O. 2 pills tid.66ISR
Plus placebo P.O. 2 pills tid.

REN DD
2016
RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Metoprolol tartrate P.O. 25 mg bid, Rosuvastatin P.O. 10 mg qd.
RWM plus Huoxue tongmai decoction P.O. 200 ml bid.66ISR
LI QZ
2016
RWM:Clopidogrel P.O.75 mg qd, Aspirin P.O. 100 mg qd,
Atorvastatin P.O. 10 mg qd.
RWM plus Guanxin tongluo capsule P.O. 1.6 g tid66ISR,
Response rate of ECG

SUN QY
2016
RWM:Aspirin P.O. 100 mg qd, Benazepril hydrochloride P.O. 10 mg qd,
Clopidogrel P.O. 75 mg qd, Isosorbide mononitrate P.O. 25 mg tid,
Metoprolol tartrate P.O. 12.5 mg bid, Simvastatin P.O. 10 mg qd.
RWM plus Yixin tongmai decoction P.O. 1/2 dose bid.66ISR

XU MT 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Atorvastatin P.O. 10 mg qd
RWM plus Guanxin suhe wan P.O. 30 g tid.66ISR

MENG XL 2016RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Atorvastatin P.O. 20 mg qd, Valsartan P.O. 80 mg qd,
Metformin P.O. 0.5 g bid.
RWM plus Yiqi Huoxue Jiedu decoction P.O. 300 ml bid.66ISR,
Angina recurrence

YANG TL 2016 RWM:Aspirin P.O. 100 mg qd, Clopidogrel P.O. 75 mg qd,
pioglitazone 30 mg/d, ACEI/ARB, Beta blocker, Statins.
RWM plus Tongxinluo capsule P.O. 1.04 g tid.1212ISR, CD,
Angina recurrence,
MI, MLD, LLL
plus placebo P.O. 1.04 g tid.

WANG X 2016RWM:Aspirin P.O.100 mg qd, Clopidogrel P.O. 75 mg qd,
Atorvastatin P.O. 20 mg qd, Isosorbide mononitrate P.O. 40 mg qd,
Metoprolol P.O. 23.75 mg qd.
RWM plus Huoxue yiqi tongmai decoction 100 ml bid.66ISR,
MI, PCI, MLD,
Angina recurrence

ZHOU W 2015RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O.0.1 g qd,
Simvastatin P.O. 20 mg qd, Glyceryl trinitrate P.O. 0.5 mg prn.
RWM plus Longzhi dispensing granules P.O. 36 g tid.66ISR
PENG WD 2015RWM:Clopidogrel P.O. 75 mg qd,
Aspirin P.O. 0.5 g qd,
Atorvastatin P.O. 10 mg qd,
Metoprolol tartrate P.O. 75 mg qd.
RWM plus Mailuo shutong capsule P.O. 0.84 g tid66ISR,
Response rate of ECG

ZHANG Y 2015RWM:Aspirin, Clopidogrel, Nitrates, ACEI, Beta blocker, Statins.RWM plus No. 1 Xintong prescription P.O. 100 ml bid.66ISR

WANG K 2015RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 100 mg qd,
Atorvastatin P.O. 40 mg qd, Metoprolo P.O. 25 mg qd.
RWM plus Xuefu zhuyu capsule P.O. 3 pills tid.1212ISR, CD,
Angina recurrence

LU HW 2014RWM:Aspirin, Clopidogrel, Nitrates, ACEI, Beta blocker, Statins, CCB.RWM plus Tongxinluo capsule P.O. 3 pills tid.1212ISR, CD, MI, LLL,
Angina recurrence

ZHANG PF 2014RWM:Clopidogrel P.O. 75 mg qd, Atorvastatin P.O. 20 mg qd,
Metoprolol tartrate P.O. 12.5 mg bid.
RWM plus Xinmai futong decoction P.O. 1/2 dose bid.66ISR, LLL, Angina recurrence

SHI QJ 2014RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O. 0.1 g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Yiqi huayu jiedu decoction P.O. 1/2 dose bid.66ISR,
Response rate of ECG

CHEN K 2014RWM:Aspirin, Clopidogrel, Statins, ACEI, Beta blocker, nitrates, CCB.RWM plus No. 2 Xintong prescription P.O. 200 ml bid.66ISR

LI B
2014
RWM:Aspirin, Clopidogrel, Nitrates, Beta blockers, Statins.RWM plus Qishen yiqi droplets P.O. 0.5 tid.66ISR, Angina recurrence,
Response rate of ECG

LI CW
2014
RWMRWM plus Qishen yiqi droplets P.O. 0.5 tid.99ISR
WANG ZQ 2013RWM:Aspirin P.O.0.1 g qd, Clopidogrel P.O. 75 mg qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Qiwei sanxiong decotion P.O. 150 ml bid.66ISR,
Angina recurrence

ZHANG Q 2013RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O.0.1 g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Shenshao oral lotion P.O. 10 ml tid.1212ISR,
MLD, LLL

DENG XD 2013RWM:Aspirin P.O.300 mg/d, Clopidogrel P.O. 75 mg/d.RWM plus Tongxinluo capsule P.O. 4 pills tid66ISR,
MLD

CHEN K 2013RWM:Aspirin, Clopidogrel, Statins, ACEI, Beta blockers, Nitrates, CCB.RWM plus No. 3 Xintong prescription P.O. 100 ml bid.1212ISR

SI XC 2013RWMRWM plus Shexiang baoxin wan P.O. 2 pills tid.618ISR, CD, MI, Angina recurrence,
Revascularization

HAN P 2012RWM:Aspirin P.O. 300 mg (0–3 m),75–150 mg qd (3–6 m)
Clopidogrel P.O. 75 mg qd.
RWM plus combined decoction (Gualou xiebai banxia decoction, Xuefu zhuyu decoction) P.O. 100 ml bid.66ISR

REN XY 2012RWM:Aspirin, Clopidogrel, nitrate, Statins, ACEI.RWM plus Yiqi huayu decoction P.O. 100 ml bid.66ISR

NIU XY 2012RWMRWM plus Jingqi danshen decoction P.O. 97 g bid.36ISR
Response rate of ECG

GAO XX 2012RWM:Aspirin, Clopidogrel, Statins.RWM plus No. 1 Xintong prescription P.O. 100 ml bid.66ISR
DAI GF 2011RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O.0.1 g qd,
Atorvastatin P.O. 20 mg qd.
RWM plus Tongxinluo capsule P.O.66ISR,
Response rate of ECG

MEI CL 2011RWM:Clopidogrel P.O. 75 mg qd, Aspirin P.O.0.1 g qd,
Simvastatin P.O. 20 mg qd.
RWM plus Xueyu decoction P.O. 100 ml bid.36ISR,
Angina recurrence

WANG XD 2010 RWM:Aspirin P.O. 300 mg (0-1m), 100 mg (1–12 m) qd,
Clopidogrel P.O. 75 mg qd, Atorvastatin P.O. 20 mg qd.
RWM plus Tongxinluo capsule P.O. 1.14 g tid.1212ISR,
Angina recurrence,
MI, CD, MLD
Plus placebo P.O. 1.14g tid.

CHENG SJ 2010RWM:Aspirin, Clopidogrel, Glyceryl trinitrate, Metoprolol, Atorvastatin.RWM plus Anxin granules P.O. 3.5 g tid.66ISR, MI, PCI

DAI GF 2010RWM:Clopidogrel P.O. 75 mg qd, Atorvastatin P.O. 20 mg qd.
Aspirin P.O. 100 mg qd,
RWM plus Yiqi huoxue tongmai decoction P.O. 250 ml bid.1212ISR,
Response rate of ECG

LIU LL 2010RWM:Clopidogrel P.O. 75 mg qd, Atorvastatin P.O. 20 mg qd.
Aspirin P.O. 100 mg qd,
RWM plus Jingtian zaitong capsule P.O. 10 g tid.66ISR,
Response rate of ECG

EG = experimental group; CG = control group; RWM = routine western medicine; ECG = electrocardiogram; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blockage; CD = cardiac death; MI = myocardial Infarction; MLD = minimum lumen diameter; LLL = late loss of lumen; PCI = percutaneous coronary intervention; CCB = calcium channel blocker.
3.3. Methodological Quality of Included RCTs

Of the 40 included studies, 13 were randomized by random number tables or SPSS software. The other 27 studies used the phrase “randomly allocating” but did not describe the method of randomization. Only 1 trial reported allocation concealment as “by sealed, opaque envelopes”. Participants or outcome assessors were blinded in only 4 trials. All studies reported the primary outcome and clearly described the data collection methods, and we therefore believed that they were free from selective reporting bias. According to the criteria we prespecified, as shown in the Quality Assessment section, we judged the performance bias and detection bias of these studies to be low-risk. In conclusion, the overall methodological quality of the 40 trials was rated as low-risk. The details of this analysis are shown in Figure 2. The mean score for the RCTs included in this analysis was 5.15 (Table 3).

(a)

Quality assessment criteriaDAI GF
2017
CHEN K2013CHEN K2014CHENG SJ2010DAI GF
2010
DAI GF
2011
DENG XD2013GAO XX2012GONG XY2016HAN P2012LI B2014LI CW
2014
LI QZ
2016
LIU LL
2010

Random sequence generation+--+----+----+
Allocation concealment-----------+--
Blinding of participants and personnel++++++++++++++
Blinding of outcome assessment++++++++++++++
Incomplete outcome data-++++++++---++
Selective reporting++++++-+++++++
Other bias++++++++++++++
Overall quality score (maximum = 7)55565545644556

(b)

Quality assessment criteriaLU HW
2014
MEI CL
2011
MENG XL2016NIU XY2012PENG WD2015REN DD2016REN XY2012SHI QJ2014SI XC
2013
SUN QY2016TANG YY2016WANG K2015WANG KL2016

Random sequence generation+--+-+-+-+--+
Allocation concealment-------------
Blinding of participants and personnel+++++++++++++
Blinding of outcome assessment+++++++++++++
Incomplete outcome data+++++++++++-+
Selective reporting+++++++++++++
Other bias+++++++++++++
Overall quality score (maximum = 7)6556565656546

(c)

Quality assessment criteriaWANG X2016WANG XD2010WANG ZQ2013XIAO NH2016XU MT2016YANG TL2016ZHANG PF2014ZHANG Q2013ZHANG RZ2017ZHANG Y2015ZHOU JC2016ZHOU W2015ZHU HB2016

Random sequence generation+-+--------+-
Allocation concealment-------------
Blinding of participants and personnel+++++++++++++
Blinding of outcome assessment+++++++++++++
Incomplete outcome data+++++++-+++-+
Selective reporting+++++++++++++
Other bias+++++++++++++
Overall quality score (maximum = 7)6565555455555

3.4. Primary Outcomes
3.4.1. In-Stent Restenosis

Three studies provided data for the number of ISR (NoR), and the pooled estimates showed that, in patients with CAD, NoR was lower for CCM plus RWM than for RWM alone (RR 0.24, 95% CI 0.10 to 0.57, ; , ) after 6 months of follow-up. In all, 34 studies provided data on the number of cases of ISR that had a follow-up time of 6 to 18 months. The rate of ISR was obviously lower in the CCM plus RWM group than in the group treated with the same RWM alone (RR 0.44, 95% CI 0.37 to 0.53, ; , ). A meta-analysis of an additional 3 studies also showed that CCM plus RWM exerted a beneficial effect on the rate of ISR when CM placebo plus RWM was used as the control intervention with a 6- to 12-month follow-up (RR 0.34, 95% CI 0.20 to 0.57, ; , ). In addition, we evaluated these 34 studies to detect publication bias. The funnel plot was asymmetrical, indicating publication bias. Because funnel plot is used as a qualitative method to detect the publication bias of an article, we also used Egger’s method to detect publication bias, and the results again implied the presence of publication bias . The details of these analyses are shown in Figures 35 and Table 4.


Std_EffCoef.Std. Err.[95% Conf. Interval]

slope−.192833.1590705−1.210.234−0.5168491.1311831
bias−1.155985.3911951−3.970.000−1.74913−.56284

3.4.2. Subgroup Analysis

Different types of Western medicine were used among the 34 studies, and we therefore performed a subgroup analysis. In 25 studies, a better benefit was exerted on ISR by CCM plus RWM (DAPT, DAPT + Statin, DAPT + β-blocker + Statin, Nitrates + DAPT + ACEI/ARB + β-blocker + Statin, Nitrates + DAPT + ACEI/ARB + β-blocker + Statin + CCB) than the RWM alone. In 4 studies, there was no significant difference between the CCM plus RWM (Nitrates + DAPT + Statin, Nitrates + DAPT + ACEI/ARB + β-blocker + Statin) group and the RWM group (Table 5 and Figure 6).


RWMStudies RR (95% CI)

DAPT40.32 [0.18, 0.57]0%
DAPT + Statin130.45 [0.32, 0.64]0%
DAPT + β-blocker + Statin40.36 [0.20, 0.64]0%
DAPT + ACEI/ARB + Statin + Metformin1
Nitrates + DAPT + Statin20.36 [0.12, 1.08]0%
Nitrates + DAPT + ACEI/ARB + Statin1
Nitrates + DAPT + β-blocker + Statin20.58 [0.24, 1.42]0%
Nitrates + DAPT + ACEI/ARB + β-blocker + Statin20.39 [0.21, 0.70]70%
Nitrates + DAPT + ACEI/ARB + β-blocker + Statin + CCB20.57 [0.37, 0.86]0%
Unclear3

Difference in the dosage forms of drugs (e.g., decoction, granules, pills, capsules, and tablets) might impact results, and we therefore carried out a subgroup analysis. A pooled estimate of cases of ISR showed that there was a significant difference between the decoction plus RWM and RWM alone groups in 18 studies (RR 0.28, 95% CI = 0.20 to 0.38, ; , ). No additional benefit was exerted in ISR in the granules plus RWM group than in the RWM alone group (RR 0.39, 95% CI 0.13 to 1.21, ; , ). A meta-analysis of another 3 studies also showed that there was no significant difference between the pills plus RWM group and the RWM alone group (RR 0.59, 95% CI 0.34 to 1.01, ; , ). There were significantly fewer cases of ISR in the capsules plus RWM group than in the group treated with the same RWM alone (RR 0.49, 95% CI 0.36 to 0.67, ; , ). The details of these analyses are shown in Table 6 and Figure 7.


CCM Studies RR (95% CI)

decoction180.35 [0.26, 0.46]0%
granules20.39 [0.13, 1.21]0%
pills30.59 [0.34, 1.01]0%
capsules90.49 [0.36, 0.67]0%
tablets1

The association between the use of CCM plus RWM and RWM alone remained significant after the sensitivity analysis excluding studies with low quality score (quality score  ⩽ 4) with a pooled RR of 0.41 (95% CI, 0.34–0.50). (Figure 8).

3.4.3. Adverse Reactions

Only 2 studies reported the details of adverse reactions related to CCM, including hepatic dysfunction, gingival bleeding, diarrhoea, stomach discomfort, flushing, dizziness, and headache. More adverse reactions were reported in patients treated with a Huoxue yiqi decoction and a Shenshao decoction, but most of these reactions were not severe and disappeared without special treatment. There was no significant difference in adverse reactions between the CCM plus RWM and RWM alone groups (Table 7 and Figure 9).


StudyIntervention EG CGRR [95% CI]
EETotalEETotal

WANG X 2016Huoxue yiqi decoction plus RWM versus RWM8645641.60 [0.55, 4.63]
ZHANG Q 2013Shenshao Oral Lotion plus RWM versus RWM247314772.02 [0.18, 22.17]

EG = experimental group; CG = control group; EE = events.
3.5. Secondary Outcomes
3.5.1. Major Adverse Cardiac Events (Table 8)

Revascularization. Revascularization was reported in 3 studies, in which 308 patients were treated with 3 different CCMs, including Anxin granules, Shexiang baoxin pills, and a Huoxue yiqi tongmai decoction. After 6–18 months of follow-up, the rate of revascularization was not significantly different between the CCM plus RWM and the RWM alone groups (RR 0.33, 95% CI 0.07 to 1.62, ; , ) (Figure 10).


MACENo. of studies/patientsFollow-up
(mos.)
Pooled estimate
(RR, 95% CI)

Revascularization
(CCM plus RWM versus RWM)
3/3086–180.33 [0.07, 1.62]
Myocardial Infarction
(CCM plus RWM versus RWM)
3/3086–180.33 [0.17, 1.62]
Myocardial Infarction
(CCM plus RWM versus CM placebo plus RWM)
2/47560.42 [0.11, 1.60]
Cardiac Mortality
(CCM plus RWM versus RWM)
5/92112–180.25 [0.03, 2.21]
Recurrent Angina
(CCM plus RWM versus RWM)
9/10956–180.50 [0.38, 0.65]
Recurrent Angina
(CCM plus RWM versus CM placebo plus RWM)
2/47560.32 [0.19, 0.54]

Myocardial Infarction. Myocardial infarction (MI) was reported in 5 studies, in which 783 patients were treated with 4 different CCMs, including Anxin granules, Shexiang baoxin pills, Tongxinluo capsules, and a Huoxue yiqi tongmai decoction. During approximately 6–18 months of follow-up, no significant difference was found between the CCM plus RWM group and the RWM alone group (RR 0.33, 95% CI 0.07 to 1.62, ; , ). A meta-analysis of the other 2 studies also showed that there was no significant difference between the CCM plus RWM group and the CM placebo plus RWM group (RR 0.42, 95% CI 0.11 to 1.60, ; , ) after 6 months of follow-up (Figure 11).

Cardiac Mortality. In 5 studies of 4 kinds of CCM, 461 patients were included in the treatment group, and 460 patients were included in the control group. Cardiac death was recorded as a measure of effect during a 12–18-month follow-up period. No cardiac deaths occurred in any of the groups in three of the studies or in the experimental group in the other 2 studies. A pooled estimate of cardiac deaths showed that there was no significant difference between the CCM plus RWM and RWM alone groups in the latter two studies (RR 0.25, 95% CI = 0.03 to 2.21; ; , ) (Figure 12).

Recurrent Angina. Recurrent angina was reported in 11 studies involving 1570 patients. During a 6–18-month follow-up period, the rate of recurrent angina was significantly lower in the CCM plus RWM group than in the groups treated with the same RWM alone (RR 0.50, 95% CI 0.38 to 0.65, ; , ) or with a CM placebo plus the same RWM (RR 0.32, 95% CI 0.19 to 0.54, ; , ) (Figure 13).

Angiographic Measurements. Follow-up angiography performed in patients with ISR at 6–12 months after the index PCI in 7 studies that evaluated 4 Chinese Herbal Medicines (CHMs) in 1917 patients. Baseline information showed that the mean minimal luminal diameter (MLD) before and immediately after the index PCI and the gain in luminal diameter following stent placement were comparable between groups.

MLD is defined as the smallest diameter in the treated lesion area [53] and was reported in 5 studies (Table 9). MLD was significantly better in the CCM plus RWM group than in the CM placebo plus RWM when patients were treated with Tongxinluo capsules ( 1.27 mm, 95% CI 1.01 to 1.53 mm; = 0.35 mm, 95% CI 0.27 to 0.43 mm) and in the CCM plus RWM group than in the group treated with the same RWM alone when a Huoxue yiqi tongmai decoction was evaluated ( 0.42 mm, 95% CI 0.35 to 0.49 mm). There was no significant difference between the groups in the studies evaluating Shenshao oral lotion ( = 0.02 mm, 95% CI −0.02 to 0.06 mm). The Tongxinluo capsule plus RWM did not improve MLD when patients were compared to those treated with the same RWM alone ( = −1.61 mm, 95% CI −1.93 to −1.29 mm).


StudyIntervention EG CGMD [95% CI]
MeanSDTotalMeanSDTotal

DENG XD 2013Tongxinluo capsule plus RWM versus RWM3.970.59315.580.6730−1.61 [−1.93, 1.29]
WANG X 2016Huoxue yiqi tongmai decoction plus RWM vs RWM2.020.22641.60.2640.42 [0.35, 0.49]
WANG XD 2010Tongxinluo capsule plus RWM versus CM placebo plus RWM2.430.62681.160.87641.27 [1.01, 1.53]
YANGN TL 2016Tongxinluo capsule plus RWM versus CM placebo plus RWM2.810.411722.460.371710.35 [0.27, 0.43]
ZHANG Q 2013Shenshao oral lotion plus RWM versus RWM2.110.384732.090.324770.02 [−0.02, 0.06]

EG = experimental group; CG = control group; MD = mean difference.

The primary angiographic endpoint was late lumen loss (LLL) after 6 to 12 months. LLL was evaluated by determining the difference between the minimum lumen diameter after the procedure and at follow-up using quantitative coronary angiography [54]. LLL was measured in 4 studies of 3 CHMs after 6 and 12 months of follow-up (Table 10). There was a significant difference between the CHM plus RWM group and the control group treated with the same RWM alone when the CHM being tested was Tongxinluo capsules ( = −0.36 mm, 95% CI −0.42 to −0.30 mm), a Xinmai futong decoction ( = −0.3 mm, 95% CI −0.41 to −0.19 mm) and a Shenshao oral lotion ( = −0.05 mm, 95% CI −0.09 to −0.01 mm). Finally, LLL was lower in the RWM plus Tongxinluo capsule group than in the group treated with the same RWM plus placebo ( = −0.24 mm, 95% CI −0.28 to −0.20 mm).


StudyIntervention EG CGMD [95% CI]
MeanSDTotalMeanSDTotal

LU HW
2014
Tongxinluo capsule plus RWM versus RWM0.430.17900.790.2490−0.36 [−0.42, 0.30]
YANGN TL 2016Tongxinluo capsule plus RWM versus CM placebo plus RWM0.210.171720.450.24171−0.24 [−0.28, 0.20]
ZHANG PF 2014Xinmai futong decoction plus RWM versus RWM0.50.21610.80.462−0.30 [−0.41, 0.19]
ZHANG Q 2013Shenshao oral lotion plus RWM versus RWM0.620.34730.670.32477−0.05 [−0.09, 0.01]

EG = experimental group; CG = control group; MD = mean difference.

In this SR, 40 studies involving 4536 CAD patients who underwent stent implantation were identified. All studies were RCTs. Approximately 75% of the studies were performed in the last five years. A domain-based evaluation showed that the mean score of the included RCTs was 5.15. Of the included studies, three were designed to compare a CCM plus RWM versus a CM placebo plus the same RWM, and 37 studies were designed to compare a CCM plus RWM versus the same RWM alone.

In this SR, all studies assessed ISR using CTA or CA. A three subgroup meta-analysis of 33 CCM plus RWM groups showed that they produced an absolute decrease in the ISR rate. Given the low risk of bias (demonstrated by analyses of methodological quality and publication bias), the following robust conclusion can be drawn: CCM plus RWM reduces ISR. Furthermore, there was no significant difference in adverse reactions between the CCM plus RWM and RWM alone groups in 2 of the studies, potentially indicating that CCM plus RWM is a safe treatment. However, further observations are needed. An Egger’s linear regression test was performed to statistically assess funnel plot asymmetry and publication bias. Substantially more studies in the literature have positive than negative results, and this produced so-called publication bias.

With regard to secondary outcomes, we concluded that CCM plus RWM did not exert a benefit against revascularization, MI and cardiac mortality during a 6–18-month follow-up period after stent implantation. This finding may be attributed to the limited number of patients and the short follow-up times reported in the studies. However, 11 studies explored CCMs plus RWMs, and recurrent angina was significantly reduced by this treatment during the 6–18-month follow-up period. This may indicate that treatment with a CCM plus RWM exerts a better effect on symptom improvement. Some studies have concluded that a major determinant of the restenosis rate is the final MLD after all interventions [55]. MLD can be evaluated as a continuous end point from 6 to 9 months after intervention and is precisely associated with stable long-term results in the treated coronary segment [56]. In addition, LLL is monotonically correlated with the probability of restenosis and, when evaluated, is a more efficient estimate of restenosis progress in this era of lower binary restenosis rates [54]. Hence, MLD and LLL are two major determinants of the restenosis rate. In this SR, 7 studies that evaluated 4 CHMs reported MLD and LLL. Although pooled results were not available for either MLD or LLL because there was high heterogeneity ( or ), in most of the studies, CCM plus RWM exerted significant beneficial effects.

Specifically, Tongxinluo capsules appeared to markedly reduce the rates of ISR, recurrent angina, and LLL and improve MLD. Qiwei sanxiong decoction [37] appeared to markedly reduce the rates of ISR and recurrent angina. Yiqi huoxue huayu decoction [24], Yiqi huayu decoction [43], Yixin tongmai decoction [22], and Yiqi tongluo huatan decoction [16] each provided significant benefits by reducing the rate of ISR. Qishen yiqi droplets [35] exerted significant benefits by reducing recurrent angina. Most of the above-described CCMs are meant to supplement Qi and activate the blood. Their main ingredients are Huangqi (astragalus), Renshen (Panax), Shaoyao (peony), Danshen (salvia), and Chuanxiong (tetramethylpyrazine).

The pathogenesis of restenosis is not yet fully understood. However, it is generally accepted that when a stent causes injury to a coronary artery, it triggers a series of inflammatory reactions that result in the migration and proliferation of vascular smooth muscle cells (SMCs) within the vessel lumen and neointimal hyperplasia. In TCM, CAD is thought to be a result of “Qi deficiency and Blood Stasis”. The severity of Blood Stasis syndrome is significantly correlated with the complexity of coronary lesions and the degree of stenosis and is an important factor affecting the occurrence of restenosis after PCI [57]. Many studies have demonstrated that Astragalus [58], salvia [59], tetramethylpyrazine [60], and Chuangxingol and paeoniflorin [61], which are main ingredients in TCM, play effective anti-inflammatory roles and inhibit SMC proliferation and migration. This may be the mechanism by which the above-mentioned CCMs prevent and treat restenosis.

Ideally, RCTs should adhere to known research design standards. In our examination of these studies, we did not have access to enough details related to these characteristics, although the baselines were comparable between comparison groups in the included studies. Details about randomization methodology were also lacking. In the 40 studies we reviewed, 11 reported that they implemented randomization using a random number table or a computer random number generator, such as SPSS software, and only 1 mentioned using sealed, opaque envelope concealment. Participants or outcome assessors were blinded in only 4 of the trials. In addition, studies that involve therapeutic trials should also report the rates of adverse reactions regardless of whether or not they occur. Reporting of adverse reactions is very important for evaluating the safety of interventional measures even though there is no guarantee that the adverse reactions were related to the interventional measure. Subgroup analyses showed that different types of Western medicines and drug forms affected outcomes. Furthermore, most of the 40 studies failed to mention the type of stent that was deployed (i.e., whether it was a bare metal stent or a drug-eluting stent). Therefore, the difference in the curative effects observed between the CCM plus RWM and control groups is uncertain, and there is bias in our results. In our review, only 11 of the 40 included trials reported adverse reactions, rendering it difficult to systematically evaluate the safety of the evaluated CCMs in ISR. Future research on these topics will help to clarify the effectiveness and safety of CCMs in ISR.

4. Conclusions

Based on the results of this SR, we conclude combining RWM with CCMs may provide moderate efficacy in preventing ISR following PCI with stent placement. This is despite the fact that our investigation revealed the potential presence of bias in the identified studies. CCMs used to supplement Qi and activate the blood are suggested for preventing and treating restenosis. In addition, additional experimental studies should explore the mechanisms by which the main ingredients in CCM act to supplement Qi or activating the blood to prevent and treat restenosis. Future rigorously designed RCTs that explore CCM plus RWM therapies aimed at preventing post-PCI ISR should adhere to established design standards to overcome the limitations presented in this review. In particular, they should ensure adequate concealment of allocation and blinding of primary outcomes assessors.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

Qian Lin and Lu Liu conceived this SR. Lu Liu, Jing Liu, and Qun Gao drafted and revised this SR. Jinjin Lu, Jie Wan, Yan Li, Xiaoyun Cui, and Kun Zhou established the Data Management Committee and were separately responsible for study selection, data extraction, and risk of bias assessment procedures. Wenhao Jia, Yanchao Huang, and Wenbai Qu took charge of coordinating each process of this study, settling disagreements, and ensuring data safety. Qian Lin and Lu Liu contributed to the design of the statistical analyses. Lu Liu and Yang Wu were responsible for the overall data synthesis and analysis. Jing Liu contributed to polishing the language of the text. Qian Lin was responsible for the overall quality of this SR. All authors have read this manuscript and approved the publication of this SR.

Acknowledgments

This study is supported by the National Natural Science Foundation of China (no. 8160150703).

References

  1. E. D. Grech, “ABC of interventional cardiology: percutaneous coronary intervention. I: history and development,” British Medical Journal, vol. 326, no. 7398, pp. 1080–1082, 2003. View at: Publisher Site | Google Scholar
  2. J. W. Moses, M. B. Leon, J. J. Popma et al., “Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery,” The New England Journal of Medicine, vol. 349, no. 14, pp. 1315–1323, 2003. View at: Publisher Site | Google Scholar
  3. L.-P. Zhao, W.-T. Xu, L. Wang et al., “Influence of insulin resistance on in-stent restenosis in patients undergoing coronary drug-eluting stent implantation after long-term angiographic follow-up,” Coronary Artery Disease, vol. 26, no. 1, pp. 5–10, 2016. View at: Publisher Site | Google Scholar
  4. X. Wang, “Expert consensus on TCM diagnosis and treatment of chest pain after percutaneous coronary intervention (PCI),” Journal of Traditional Chinese Medicine, vol. 55, no. 13, pp. 1167–1170, 2014. View at: Google Scholar
  5. Y. Ren, K.-J. Chen, and X.-M. Ruan, “Systematic review of randomized controlled trials on preventing and treating restenosis after percutaneous coronary intervention with Chinese medicine,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 28, no. 7, pp. 597–601, 2008. View at: Google Scholar
  6. G.-H. Zheng, J.-P. Liu, N. S. Wang, H.-Y. Chen, and J.-F. Chu, “Systematic review of chinese herbal medicines for preventing in-stent coronary restenosis after percutaneous coronary intervention,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 253409, 19 pages, 2012. View at: Publisher Site | Google Scholar
  7. R. Xi, Q. Yang, K. Chen et al., “Chinese medicines for Activating Blood and Removing Blood Stasison the clinical outcome after percutaneous coronary intervention: a meta-analysis of randomized controlled trials,” Cardiology (Switzerland), vol. 129, pp. 132-133, 2014. View at: Google Scholar
  8. D. Moher, L. Shamseer, and M. Clarke, “Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement,” Systematic Reviews, vol. 4, no. 1, Article ID 1, 2015. View at: Publisher Site | Google Scholar
  9. J. P. T. Higgins and S. Green, “Cochrane handbook forsystematic reviews of interventions version 5.1.0 [updated March 2011], The Cochrane Collaboration,” http://handbook.cochrane.org, 2011. View at: Publisher Site | Google Scholar
  10. Chinese Society of Cardiology of Chinese Medical Association, Chinese College of Cardiovascular, and Editorial Board of Chinese Journal of Cardiology, “Chinese guidelines for percutaneous coronary intervention,” Chinese Journal of Cardiology, vol. 44, no. 5, pp. 382–400, 2016. View at: Google Scholar
  11. J. P. Higgins, D. G. Altman, and P. C. Gøtzsche, “The Cochrane collaboration's tool for assessing risk of bias in randomized trials,” British Medical Journal, vol. 343, p. d5928, 2011. View at: Google Scholar
  12. G. F. Dai, B. Z. zhang, and F. Wang, “Research of Tongmai decoction in the prevention and treatment of restenosis in patients with Qi Deficiency and Blood Stasis syndrome after percutaneous coronary intervention,” Chinese Journal of Integrative Medicine on Cardio-/Cerebrovascular Disease, vol. 15, no. 2, pp. 136–142, 2017. View at: Google Scholar
  13. R. Z. Zhangand and A. S. Gao, “Clinical observation on activating blood circulation and removing blood stasis medicine in the prevention and treatment of restenosis after coronary artery stenting,” Guangming Journal of Chinese Medicine, vol. 32, no. 8, pp. 1083–1085, 2017. View at: Google Scholar
  14. K. L. Wangand and Z. K. Yu, “Clinical effect of Huxinkang tablets in treatment of restenosis after percutaneous coronary interventionin patients with coronary heart disease,” Hunan Journal of Traditional Chinese Medicine, vol. 32, no. 12, pp. 7–9, 2016. View at: Google Scholar
  15. X. Y. Gong, “The effect of Huoxue tongmai fang in preventing coronary restenosis on ECG changes after coronary intervention,” China Prescription Drug, vol. 14, no. 9, pp. 102-103, 2016. View at: Google Scholar
  16. Y. Y. Tang and B. Fang, “Clinical observation of Yiqi Tongluo Huatan Decoction Combined with antiplatelet drugs for in-stent restenosis after percutaneous coronary intervention in patients with coronary heart disease,” Zhejiang Journal of Traditional Chinese Medicine, vol. 51, no. 8, pp. 559-560, 2016. View at: Google Scholar
  17. J. C. Zhou and M. J. Cheng, “Clinical effect analysis of integrated traditional Chinese and western medicine therapy on the prevention of restenosis (RS) after percutaneous coronary intervention (PCI),” Clinical Journal of Chinese Medicine, vol. 15, no. 8, pp. 29–31, 2016. View at: Google Scholar
  18. H. B. Zhu, “Analysis of the efficacy of combined Statins with Mailuo shutong capsule in the prevention and treatment of restenosis in patients with coronary heart disease after PCI,” China Journal of Chinese Materia Medica, pp. 1861-1862, 2015. View at: Google Scholar
  19. N. H. Xiao, B. H. Liu, and Y. G. Zhang, “Clinical study of rosuvastatin combined with Xinxuetong Capsule in prevention of restenosis after coronary stent implantation,” Journal of New Chinese Medicine, vol. 48, no. 3, pp. 25–27, 2016. View at: Google Scholar
  20. D. D. Ren, H. L. Jia, Y. K. Guo et al., “Effects of Huoxue Tongmai Tang combined with western medicine to restenosis in patients after coronary artery stenting,” Journal of Traditional Chinese Medicine, vol. 57, no. 4, pp. 311–315, 2016. View at: Google Scholar
  21. Q. Z. Li, G. Hu, and Y. L. Wang, “Clinical observation of Guanxin Tongluo Capsule combined with dual antiplatelet drugs in prevention and treatment of in-stent restenosis of 34 patients with coronary heart disease after PCI,” Guiding Journal of Traditional Chinese Medicine and Pharmacy, vol. 22, no. 3, pp. 80–82, 2016. View at: Google Scholar
  22. Q. Y. Sun, “Efficacy of combination of traditional Chinese medicine and Western medicine in prevention and treatment of restenosis after coronary stent implantation,” Journal of New Chinese Medicine, vol. 48, no. 2, pp. 31–33, 2016. View at: Google Scholar
  23. M. T. Xu, Y. F. Chang, and X. Y. Wang, “Clinical observation of Guanxin suhe wan Combined with dual antiplatelet drugs in the Prevention and Treatment of Restenosis in in-stent restenosis after percutaneous coronary intervention,” Guiding Journal of Traditional Chinese Medicine and Pharmacology, vol. 22, no. 2, pp. 71–73, 2016. View at: Google Scholar
  24. X. L. Meng, “Clinical efficacy observation of replenishing Qi, activating blood circulation and removing toxics method on coronary restenosis after PCI,” Clinical Journal of Chinese Medicine, vol. 8, no. 3, pp. 34–38, 2016. View at: Google Scholar
  25. T. L. Yang, S. J. Pan, X. F. Zhang et al., “Effect of Tongxinluo capsule combined with pioglitazone for treatment of coronary stent restenosis in patients with coronary heart disease and type 2 diabetes: a prospective randomized double-blind placebo-controlled study,” Chinese Journal of Integrated Traditional and Western Medicine in Intensive and Critical Care, vol. 23, no. 4, pp. 341–347, 2016. View at: Google Scholar
  26. X. Wang, K. Y. Cheng, Z. W. Jia et al., “Clinical observation of coronary artery intervention for acute myocardial infarction with Huoxue Yiqi Tongmai Yin,” Journal of Emergency in Traditional Chinese Medicine, vol. 25, no. 7, pp. 1415–1417, 2016. View at: Google Scholar
  27. W. Zhou, X. B. Zhao, M. Zhou et al., “Effect of Longzhi dispensing granule on prevention and treatment of coronary restenosis after PCI,” Journal of Tianjin Universityof Traditional Chinese Medicine, vol. 34, no. 5, pp. 265–269, 2015. View at: Google Scholar
  28. W. D. Peng, B. Dong, and Y. Zhou, “Clinical observation on Mailuo shutong capsule combined with atorvastatin on restenosis of 32 patients with coronary artery disease after PCI,” Guiding Journal of Traditional Chinese Medicine and Pharmacy, vol. 21, no. 18, pp. 69–71, 2015. View at: Google Scholar
  29. Y. Zhang, D. S. Wang, and X. X. Gao, “Clinical research on preventing of No. 1 Xintong prescription on ISR,” Guiding Journal of Traditional Chinese Medicine and Pharmacy, vol. 21, no. 15, pp. 26–27, 32, 2015. View at: Google Scholar
  30. K. Wang, J. Zhang, and Y. J. Du, “Effects of Xuefuzhuyu capsules on the restenosis of AMI after percutaneous coronary intervention (PCI) in elderly patients,” Practical Clinical Journal of Integrated Traditional Chinese and Western Medicine, vol. 15, no. 2, pp. 3–5, 2015. View at: Google Scholar
  31. H. W. Lu, J. Zhang, X. Chen et al., “Clinical observation on Tongxinluo capsule combined with routine western medicine in the prevention of restenosis after percutaneous coronary intervention in 90 cases,” Journal of Traditional Chinese Medicine, vol. 55, no. 24, pp. 2117–2110, 2014. View at: Google Scholar
  32. P. F. Zhangand and H. C. Zhu, “Effect of Xinmai futong fang on restenosis after coronary stent implantation,” Clinical Journal of Traditional Chinese Medicine, vol. 26, no. 11, pp. 1133-1134, 2014. View at: Google Scholar
  33. Q. J. Shi, “Treatment of restenosis of 30 patients with coronary heart disease after PCI by Yiqi Huayu Jiedu decoction,” Traditional Chinese Medicinal Research, vol. 27, no. 9, pp. 36–38, 2014. View at: Google Scholar
  34. K. Chen, X. X. Gao, and Y. Zhang, “Clinical research on preventing of No. 2 Xintong prescription on ISR,” Shandong Journal of Traditional Chinese Medicine, vol. 33, no. 4, pp. 290-291, 2014. View at: Google Scholar
  35. B. Li, “Effect of Qishen yiqi droplet on in-stent restenosis after coronary stent implantation,” China Health Care & Nutrition, vol. 5, pp. 2877-2878, 2014. View at: Google Scholar
  36. C. W. Li, “Effects of qishen yiqi drop pill on coronary blood flow and left ventricular function in patients with anterior wall AMI after PCI,” Chinese Journal of Integrative Medicine on Cardio-/Cerebrovascular Disease, vol. 12, no. 12, pp. 1441–1443, 2014. View at: Google Scholar
  37. Z. Q. Wang, “Clinical efficacy and mechanism analysis of TCM and western medicine therapy to prevent percutaneous coronary intervention (PCI) restenosis (RS),” Chinese Archives of Traditional Chinese Medicine, vol. 31, no. 12, pp. 2819–2822, 2013. View at: Google Scholar
  38. Q. Zhang, S. K. Liu, Y. X. Li et al., “The effect of Shenshao oral lotion to restenosis after percutaneous coronary intervention,” Chinese Journal of Arteriosclerosis, vol. 21, no. 10, pp. 903–906, 2013. View at: Google Scholar
  39. X. D. Deng, “Effect of Tongxinluo Capsuleon restenosis after PCI in patients with CHD,” China Medicine and Phamacy, vol. 3, no. 12, pp. 67-68, 2013. View at: Google Scholar
  40. K. Chen, X. X. Gao, and Y. Zhang, “Clinical research on preventing of No. 2 Xintong prescription on ISR,” Journal of Sichuan of Traditional Chinese Medicine, vol. 31, no. 11, pp. 76-77, 2013. View at: Google Scholar
  41. X. C. Si and Y. P. Jia, “Effect of Shexiang Baoxin pellet on long-term prognosis in patients with coronary disease under PCI,” Clinical Journal of Chinese Medicine, vol. 5, no. 1, pp. 5-6, 2013. View at: Google Scholar
  42. P. Han, “Clinical observation of Gualou Xiebai Banxia decoction combined with Xuefu Zhuyu decoction in prevention and treatment coronary artery in-stent restenosis,” Chinese Medicine, vol. 28, no. 26, 172 pages, 2012. View at: Google Scholar
  43. X. Y. Ren, X. X. Gao, K. Chen et al., “Clinical observation of supplementing Qi and activating blood stasismethod combined with western medicine in prevention of restenosis after coronary stent implantation,” Journal of Sichuan of Traditional Chinese Medicine, vol. 30, no. 9, pp. 68-69, 2012. View at: Google Scholar
  44. X. Y. Niu, Y. Zhao, X. S. Zhang et al., “Intervention with Jingqi Danshen decoction on restenosis of 41 patients with coronary artery disease after PCI,” Journal of Traditional Chinese Medicine, vol. 53, no. 17, pp. 1503-1504, 2012. View at: Google Scholar
  45. X. X. Gao and Y. Zhang, “Clinical observation of No. 1 Xintong Prescription in prevention and treatment of restenosis after percutaneous coronary intervention in 30 cases,” Hebei Journal of Traditional Chinese Medicine, vol. 34, no. 6, pp. 832-833, 2012. View at: Google Scholar
  46. G. F. Dai and S. J. Yang, “Clinical observation of Tongxinluo capsulein the treatment of restenosis after PCI,” Guangming Journal of Chinese Medicine, vol. 26, no. 9, pp. 1823-1824, 2011. View at: Google Scholar
  47. C. L. Mei, Y. Xu, and X. Q. Shi, “Blood Stasisparty to the joint western medicine control percutaneous coronary angioplasty restenosis after 61 cases clinical observation,” Guiding Journal of Traditional Chinese Medicine and Pharmacy, vol. 17, no. 6, pp. 35-36, 2011. View at: Google Scholar
  48. X. D. Wang and B. Lou, “Effect of Tongxinluo capsule on restenosis after coronary artery stent implantation in patients with type-2 diabetes mellitus,” Journal of Nanjing University of Traditional Chinese Medicine, vol. 26, no. 6, pp. 464–467, 2010 (Chinese). View at: Google Scholar
  49. S. J. Cheng, H. B. Fang, J. S. He, and etal., “Effect of Anxin granule on the restenosis after percutaneous coronary intervention,” Journal of Traditional Chinese Medicine, vol. 51, no. 7, pp. 603–606, 2010. View at: Google Scholar
  50. G. F. Dai, H. B. Yang, and T. H. Du, “Intervention of Yiqi Huoxue Tongmai decoction on restenosis of 49 cases with coronary artery disease after PCI,” Liaoning Journal of Traditional Chinese Medicine, vol. 37, no. 6, pp. 1082-1083, 2010 (Chinese). View at: Google Scholar
  51. L. L. Liu and P. Y. Zhang, “Clinical study on prevention and treatment of restenosis after coronary intervention by Jingtian zaitong capsule,” Jilin Journal of Traditional Chinese Medicine, vol. 30, no. 1, pp. 35-36, 2010. View at: Google Scholar
  52. The Joint International Society and Federation of Cardiology/World Health Organization task force, “Nomenclature and criteria for diagnosis of ischemic heart disease,” Circulation, vol. 59, no. 3, pp. 607–609, 1979. View at: Google Scholar
  53. R. E. Kuntz and D. S. Baim, “Defining coronary restenosis: newer clinical and angiographic paradigms,” Circulation, vol. 88, no. 3, pp. 1310–1323, 1993. View at: Publisher Site | Google Scholar
  54. L. Mauri, E. J. Orav, A. J. O'Malley et al., “Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents,” Circulation, vol. 111, no. 3, pp. 321–327, 2005. View at: Publisher Site | Google Scholar
  55. K. M. Lin, D. H. Heand, and W. H. Li, “Impact of stent over-expansion at distal edge: insights from a 12-month follow-up study,” European Review for Medical and Pharmacological Sciences, vol. 19, no. 10, pp. 1874–1880, 2015. View at: Google Scholar
  56. T. Kimura, H. Yokoi, Y. Nakagawa et al., “Three-year follow-up after implantation of metallic coronary-artery stents,” The New England Journal of Medicine, vol. 334, no. 9, pp. 561–566, 1996. View at: Publisher Site | Google Scholar
  57. G. Yu and J. Wang, “Blood stasis syndrome of coronary heart disease: a perspective of modern medicine,” Chinese Journal of Integrative Medicine, vol. 20, no. 4, pp. 300–306, 2014. View at: Publisher Site | Google Scholar
  58. S. Ohkawara, Y. Okuma, T. Uehara, T. Yamagishi, and Y. Nomura, “Astrapterocarpan isolated from Astragalus membranaceus inhibits proliferation of vascular smooth muscle cells,” European Journal of Pharmacology, vol. 525, no. 1–3, pp. 41–47, 2005. View at: Publisher Site | Google Scholar
  59. L. Sun, R. Zhao, L. Zhang et al., “Salvianolic acid A inhibits PDGF-BB induced vascular smooth muscle cell migration and proliferation while does not constrain endothelial cell proliferation and nitric oxide biosynthesis,” Molecules, vol. 17, no. 3, pp. 3333–3347, 2012. View at: Publisher Site | Google Scholar
  60. G. Ma, S. Ding, Y. Feng, C. Shen, L. Chen, and Z. Chen, “Tetramethylpyrazine-eluting stents prevented in-stent restenosis in a porcine model,” Journal of Cardiovascular Pharmacology, vol. 50, no. 2, pp. 201–205, 2007. View at: Publisher Site | Google Scholar
  61. H. Xu, D. Shi, and K. Chen, “Inhibition of vascular remodelling in a porcine coronary injury model by herbal extract XS0601,” Chinese Medicine, 2006, http://www.cmjournal.org/content/1/1/2. View at: Google Scholar

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