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TYPE Review
PUBLISHED 07 June 2023
DOI 10.3389/fcvm.2023.1100006

Efficacy and safety of Danlou

tablets in traditional Chinese
EDITED BY
Tommaso Gori,
Johannes Gutenberg University Mainz,
medicine for coronary heart
Germany

REVIEWED BY
disease: a systematic review and
Bao Li,
Beijing University of Technology, China meta-analysis
Lin Li,
Tianjin University of Traditional Chinese
Medicine, China
WeiLi Mao1†, Peng Lu2†, Renhong Wan3, Kaili Mao1, Yanzhu Lv3,
Li Liang, Jie Hu1, Zhenling Fu1 and Jun Wang1*
Xuzhou Medical University, China 1
Department of Pharmacy, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou
*CORRESPONDENCE People’s Hospital, Quzhou, China, 2Department of Pharmacy, Suzhou TCM Hospital Affiliated to Nanjing
Jun Wang University of Chinese Medicine, Suzhou, China, 3School of Acupuncture and Tuina, Tianjin University of
[email protected] Traditional Chinese Medicine, Tianjin, China
†
These authors have contributed equally to this
work and share first authorship
Background: Danlou tablets exert auxiliary advantages in treating coronary heart
disease (CHD), but a summary of evidence-based proof is lacking. This study
RECEIVED 16 November 2022
ACCEPTED 09 May 2023
aims to systematically evaluate Danlou tablets in treating CHD from two aspects,
PUBLISHED 07 June 2023 including efficacy and safety.
CITATION
Methods: By a thorough retrieval of the four English databases, namely, PubMed,
Mao W, Lu P, Wan R, Mao K, Lv Y, Hu J, Fu Z and The Cochrane Library, Embase, and Web of Science, and the four Chinese
Wang J (2023) Efficacy and safety of Danlou databases, namely, CNKI, Wanfang, VIP database, and China Biomedical
tablets in traditional Chinese medicine for Literature Service System, we found all randomized controlled trials (RCTs)
coronary heart disease: a systematic review and
related to Danlou tablets in treating CHD. The retrieval time was from the
meta-analysis.
Front. Cardiovasc. Med. 10:1100006.
construction of the database to April 2022. We engaged two researchers to
doi: 10.3389/fcvm.2023.1100006 screen the studies, extract the required data, and assess the risk of bias. We then
COPYRIGHT
used RevMan5.3 and STATA.14 software to conduct a meta-analysis. The
© 2023 Mao, Lu, Wan, Mao, Lv, Hu, Fu and Grading of Recommendations Assessment, Development, and Evaluation
Wang. This is an open-access article distributed (GRADE) was used to evaluate the quality of outcome indicators.
under the terms of the Creative Commons
Attribution License (CC BY). The use,
Results: Seventeen RCTs involving 1,588 patients were included. The meta-analysis
distribution or reproduction in other forums is results are displayed as follows: clinical treatment effect [risk ratio (RR) = 1.22, 95%
permitted, provided the original author(s) and confidence interval (CI): 1.16, 1.28, P < 0.00001], angina pectoris duration [MD =
the copyright owner(s) are credited and that the
original publication in this journal is cited, in
−0.2.15, 95% CI: −2.91, −1.04, P < 0.00001], angina pectoris frequency [standard
accordance with accepted academic practice. mean difference (SMD) = −2.48, 95% CI: −3.42, −1.54, P < 0.00001], angina
No use, distribution or reproduction is pectoris degree [SMD = −0.96, 95% CI: −1.39, −0.53, P < 0.0001], TC [MD = −0.71,
permitted which does not comply with these
terms.
95% CI: −0.92, −0.51, P < 0.00001], TG [MD = −0.38, 95% CI: −0.53, −0.22, P <
0.00001], low-density lipoprotein cholesterol [MD = −0.64, 95% CI: −0.76, −0.51,
P < 0.00001], high-density lipoprotein cholesterol [MD = 0.16, 95% CI: 0.11, 0.21,
P < 0.00001], and adverse events [RR = 0.46, 95% CI: 0.24, 0.88, P = 0.02].

Abbreviations
CHD, coronary heart disease; RCTs, randomized controlled trials; WHO, World Health Organization; TCM,
traditional Chinese medicine; GRADE, Grading of Recommendations Assessment, Development and
Evaluation; ECG, electrocardiogram; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein
cholesterol; HDL-C, high-density lipoprotein cholesterol; RR, risk ratio; WMD, weighted mean difference;
SMD, standard mean difference; CIs, confidence intervals.

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Conclusion: The current evidence suggests that the combination of Danlou tablets and
Western medicine can enhance the efficacy of CHD and does not increase adverse events.
However, because of the limited number and quality of the included studies, the results of
our study should be treated with caution. Further large-scale RCTs are necessary to verify
the benefits of this approach.

KEYWORDS

Danlou tablet, coronary heart disease, randomized controlled trial, meta-analysis, complementary
alternative therapy

1. Introduction (41.1%) (7). Compared with Shexiang Baoxin pills, Danlou

tablets seem suitable for more CHD patients. However, in the
Cardiovascular and cerebrovascular diseases remain the dominant Clinical Application Guidelines for the Treatment of CHD of
causes of death (1). Cardiovascular disease killed 17.9 million people Chinese Patent Medicine (2020), the recommended intensity of
worldwide in 2016, according to the World Health Organization, of Danlou tablets in treating CHD is weak (14). Therefore, more
which about 34% were due to coronary heart disease (CHD). An high-quality clinical studies and standardized systematic reviews
estimated 23.3 million cardiovascular deaths will occur in 2030 (2, on Danlou tablets in treating coronary heart disease are needed.
3). CHD seriously harms human health and aggravates the public Some clinical studies on Danlou tablets in treating coronary
health burden with its extremely high mortality (1). CHD is a heart heart disease have been published. However, the design methods,
disease caused by myocardial ischemia and hypoxia resulting from efficacy evaluation criteria, and treatment courses of different
coronary atherosclerosis that causes lumen hardening, stenosis, or studies are different. Therefore, our systematic evaluation aims to
obstruction (4). CHD patients mainly present chest tightness, chest provide evidence-based support for the guidance of clinical and
pain, angina pectoris, and other symptoms, which may cause scientific medical work by evaluating the effectiveness and safety
sudden death in severe cases, significantly affecting patients’ daily of Danlou tablets in treating CHD.
lives and even threatening their lives (5).
CHD is caused by a combination of personal constitution,
genetic background, and environmental factors, and its symptoms
2. Methods
involve multiple organs and tissues, eventually spreading to the
whole body (6). In the development of the disease, different 2.1. Study registration
groups present different clinical characteristics due to differences
in personal fitness, environment, genetic background, and other This study was conducted per the guidance of the Preferred
factors. Individualized therapy has become a future development Reporting Items for Systematic Reviews and Meta-Analyses
trend in medicine (7). Traditional Chinese medicine (TCM) (PRISMA) (the checklist is shown in Supplementary Table S1).
emphasizes individualized treatment, of which the TCM syndrome In addition, the protocol and registration information can be
is the core of diagnosis and the key to treatment (6). According to found at https://www.crd.york.ac.uk/prospero/#searchadvanced
the characteristics of various symptoms, CHD is mainly divided (registration number: CRD42021274916).
into blood stasis, phlegm turbidity, cold coagulation, qi deficiency,
yin deficiency, and yang deficiency syndromes (8). For example, as
a representative of Chinese patent medicine for blood stasis 2.2. Inclusion criteria
syndrome, Shexiang Baoxin pills can improve the curative effect of
Western medicine in treating CHD according to evidence-based (1) Research type: Randomized controlled trials (RCTs) were
medical research (9) and are strongly recommended for treating included.
CHD and angina pectoris in the prevention and treatment (2) Diagnostic criteria: Patients diagnosed with CHD, which
guidelines for CHD in China (10). Danlou tablets, a representative belongs to phlegm turbidity, blood stasis, or phlegm
medicine of TCM in treating CHD with blood stasis and phlegm turbidity combined with blood stasis in TCM, were
turbidity syndrome, have the effects of clearing qi, comforting the included. CHD diagnostic criteria refer to the nomenclature
chest, relieving phlegm, dispersing the knot, invigorating blood and criteria for the diagnosis of ischemic heart disease
circulation, and eliminating stasis (11). They can also significantly formulated by the WHO (15). The TCM syndrome
reduce atherosclerosis, ischemia, and reperfusion injury and diagnostic criteria refer to the Guiding Principles for Clinical
improve myocardial dysfunction (12). Experimental studies have Research of TCM New Drugs. There is no limit on
indicated that these tablets regulate oxidative stress, prevent nationality, race, age, gender, or disease duration.
inflammation, and reduce lipid deposition (13). (3) Interventions: The treatment group was treated orally with
The results of a large-scale survey involving 5,284 patients with Danlou tablets combined with Western medicine, and the
coronary disease displayed the top three TCM syndromes: blood control group was given the same Western medicine alone
stasis (79.3%), qi deficiency (56.5%), and phlegm turbidity or combined with Danlou tablets as a placebo.

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(4) Outcome indicators: The outcomes are as follows: for any disagreement. After confirming the final included studies,
we carefully read the complete study and extracted the
(1) Primary outcomes: These involved clinical treatment
effects. According to WHO criteria, the efficacy of CHD is required data.
The extracted data included the following: (1) general
divided into the following categories (5): Significantly effective:
angina pectoris symptoms disappeared obviously and information (first author, publication year, samples in each
electrocardiogram (ECG) was normal; effective: angina pectoris group, baseline information, course of disease); (2) treatment
symptoms improved to a certain extent and the ECG was protocol (name, medication frequency, and treatment course of
improved; ineffective: angina symptoms were not relieved and oral drugs in each group); (3) risk bias assessment factors in
the ECG was not changed. The clinical treatment effect RCTs; and (4) outcome indicators.
represents the proportion of significantly and effectively effective
patients to total patients. 2.5.2. Assessment of risk of bias
(2) Secondary outcomes: These involved improvement of We assessed the risk bias according to the RCT risk
angina pectoris (including the frequency, duration, and pain assessment tool recommended by the Cochrane Collaboration
degree of angina pectoris); it was defined as an improvement of Handbook. Two researchers (PL and RW) completed risk bias
angina pectoris only when the frequency, duration, and pain assessments for each study. After completion, they cross-
degree of angina pectoris were all improved. Angina frequency checked the data, and discussion was required in case of
was defined as the number of angina attacks per day or week differences. If no agreement could be reached, negotiation with
after treatment. The duration of angina pectoris was defined as a third researcher (WM) was performed, and a final consensus
the duration of each episode of angina pectoris after the end of would be reached.
treatment, measured in minutes. The degree of pain from angina
should be evaluated as the angina score at the end of treatment. 2.5.3. Data synthesis
Blood lipid improvement [including total cholesterol (TC), RevMan5.3 software was used for data synthesis. The
triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), dichotomous variables were expressed as a relative risk ratio (RR);
and high-density lipoprotein cholesterol (HDL-C)] and the for continuous outcomes, the weighted mean difference (WMD)
incidence of adverse events were also recorded. and standard mean difference (SMD) were used as effect sizes for
consistency and inconsistency between measuring tools and
measuring units, respectively. All were presented as 95%
2.3. Exclusion criteria confidence intervals (CIs). We used χ 2 and I 2 values to determine
the heterogeneity. P ≥ 0.1, I 2 ≤ 50% indicated low heterogeneity,
(1) Studies without diagnostic criteria or with diagnostic criteria and we chose a fixed-effects model. P < 0.1, I 2 > 50% indicated
errors; significant heterogeneity, and then the heterogeneity was analyzed.
(2) Studies without outcome indicators or with incorrect or We used subgroup or sensitivity analysis to explore the origin of
incomplete data; heterogeneity and then used a random-effects model for merging
(3) Studies including patients after percutaneous coronary after excluding apparent clinical and methodological heterogeneity.
intervention (PCI); and As recommended in the Cochrane manual, one-by-one
(4) Repetitive studies or studies with duplicate study data. elimination would be used in the sensitivity analysis to test the
stability of meta-analysis results of indicators. For the primary
outcome indicators, the publication bias was qualitatively detected
2.4. Search methods for identifying studies by a funnel plot, and the potential publication bias was
quantitatively evaluated by Egger’s and Begg’s tests.
The RCTs of Danlou tablets in treating CHD were
comprehensively searched in Chinese and English databases from 2.5.4. Evidence quality evaluation
the database establishment to April 2021. Retrieval databases Two researchers (PL and RW) graded the outcome indicators
included PubMed, the Cochrane Library, CNKI, EMBASE, Web by the Grading of Recommendation, Development, and
of Science, Wanfang, and VIP database. The search terms were Evaluation (GRADE) (16). Similarly, after completing the
“Danlou tablet,” “coronary diseases,” “coronary heart diseases,” assessment, the two researchers cross-checked with each other,
“angina pectoris,” etc. Supplementary Table S2 shows the search discussed with the third researcher (WM) for any disagreement,
strategy in PubMed. and finally reached a consensus.

2.5. Data collection and analysis 3. Results

2.5.1. Data extraction and management 3.1. Studies’ characteristics
Two researchers (PL and RW) screened the literature back to
back, referring to the criteria above, and then cross-checked. A A total of 416 pieces of related literature were obtained after
third researcher (WM) discussed the results after cross checking preliminary examination, and 163 were obtained after

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FIGURE 1
Flow diagram.

eliminating duplication, of which 126 were excluded after reading while the rest (27–33) did not describe the method of
titles and abstracts, and 37 remained. The full text of 37 studies random sequence generation and were rated as unclear;
was read, and 20 articles were excluded. Finally, 17 studies only one (20) used double-blind and placebo controls, and
were included. Among the 20 excluded articles, 11 included the use of blindness and allocation hiding was rated as low
patients after PCI as intervention objects, 6 did not specify the risk, while the rest (17–19, 21–33) did not mention the use
TCM syndrome type, 2 did not conform to the intervention of blindness and allocation hiding and were rated as
plan, and 1 did not have the required outcome indicators. unclear; none of the studies (17–33) reported outcome
Figure 1 depicts a flow diagram of the literature screening indicators with incomplete information, and none of them
process. had a selective reporting; thus, their risk rating
The essential characteristics of the included studies are presented was evaluated as low. For other biases, all (17–33) were
in Table 1. Patients in the treatment group took Danlou tablets evaluated as unclear. The bias risk assessment results are
combined with Western medicine, and patients in the control presented in Table 3.
group took only Western medicine. The characteristics of the
intervention measures are presented in Table 2.

3.3. Outcome indicators

3.2. Risk of bias assessment 3.3.1. Clinical treatment effect
Fourteen RCTs (17–21, 24–26, 28–33), including 1,352
Among the 17 RCTs, 10 (17–26) were randomly assigned patients, reported the effectiveness of clinical treatment, and
by the random number table method and rated as low risk, heterogeneity test results indicated no heterogeneity (P = 0.95,

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TABLE 1 Basic characteristics of the included studies.

Study cohort No (T/C) Gender Age Course (day) Outcome

T (M/W) C (M/W) T C
Su B 2021 (17) 100/100 51/49 52/48 61.66 ± 5.52 61.59 ± 5.67 28 (1)
Tan JY 2013 (18) 60/60 39/21 39/21 62.5 ± 7 60.1 ± 9 28 (1)(2)(3)(4)
Tang RK 2013 (19) 20/20 13/7 11/9 62 ± 9.38 61.05 ± 8.55 180 (1)(2)(3)(4)(5)
Wang L 2015 (20) 30/30 18/12 16/14 64.25 ± 3.35 66.99 ± 4.11 28 (1)(2)(3)(4)(5)
Wang SH 2012 (21) 32/30 25/7 24/6 60.2 ± 9.0 62.7 ± 7.1 28 (1)(2)(3)(4)
Wang WL 2021 (22) 43/43 22/21 20/23 69.93 ± 2.04 69.84 ± 1.96 28 (2)(3)
Wang YH 2018 (23) 35/35 20/15 18/17 55.8 ± 8. 9 56.5 ± 9.2 28 (2)(3)
Wei Q 2015 (24) 40/30 22/23 24/21 52.77 ± 9.67 51.82 ± 8.86 28 (1)(2)(3)(4)(5)(6)(7)(8)(9)
Xing XH 2020 (25) 60/60 33/27 34/32 56.53 ± 5.44 55.91 ± 5.13 56 (1)(5)
Zang GP 2018 (26) 53/53 40/13 38/15 48.88 ± 5.01 49.94 ± 4.69 30 (1)(2)(3)
Ma XF 2017 (27) 40/40 28,12 25/15 58.5 ± 8.5 59.5 ± 8.5 28 (5)
Ren DZ 2014 (28) 34/34 20/14 18/16 61.2 63.5 30 (1)(5)(6)(7)(8)(9)
Tian CH 2017 (29) 47/47 28/21 27/20 58.8 ± 3.5 59.1 ± 3.5 30 (1)
Wang M 2019 (30) 50/50 28/22 29/21 60.32 ± 7.65 60.81 ± 7.94 28 (1)(5)
Yang XY 2014 (31) 41/41 23/18 28/13 — — 30 (1)(2)(3)(4)
Zang JH 2018 (32) 45/45 22/23 24/21 60.23 ± 8.12 60.06 ± 7.58 180 (1)(6)(7)(8)(9)
Zhou MJ 2013 (33) 70/70 — — — — 30 (1)(2)(3)(4)

Outcome: (1) clinical treatment effect; (2) angina pectoris frequency; (3) angina pectoris duration; (4) angina pectoris degree; (5) adverse events; (6) TG; (7) LDL-C; (8) HDL-
C; and (9) TC.

I 2 = 0%). By using a fixed-effects model, meta-analysis results tablet. Results showed significant intergroup heterogeneity of the
showed a better effect in the treatment group than in the control three subgroups: <3 g (P = 0.03, I 2 = 79%), ≥3 and <4.5 g (P <
group [(RR = 1.22, 95% CI: 1.16, 1.28, P < 0.00001)] (P < 0.05, 0.00001, I 2 = 87%), and ≥4.5 g (P < 0.00001, I 2 = 87%). Results
Table 4). Due to the difference in the daily dose of Danlou from a random-effect model are as follows: <3 g [(MD = −3.60,
tablets among the patients, we divided them into three 95% CI: −4.90, −2.30, P < 0.0001)], ≥3 and <4.5 g [(MD = −1.86,
subgroups, <3, ≥3, and <4.5, ≥4.5 g, according to the daily dose. 95% CI: −2.45, −1.27, P < 0.00001)], and ≥4.5 g [(MD = −1.72,
Heterogeneity test results indicated no significant heterogeneity 95% CI: −4.17, 0.73, P = 0.17)], indicating lower angina pectoris
of the three subgroups: <3 g (P = 0.99, I 2 = 0%), ≥3 and <4.5 g duration in the treatment group than that in the control group
(P = 0.25, I 2 = 26%), and ≥4.5 g (P = 0.99, I 2 = 0%). By using a when the daily dose of Danlou tablets was <4.5 g (P < 0.05).
fixed-effects model, the results are as follows: <3 g [(RR = 1.21, There was no difference when the daily dose of Danlou tablets
95% CI: 1.10, 1.32, P < 0.0001)], ≥3 and <4.5 g [(RR = 1.24, 95% was more significant than or equal to 4.5 g (P > 0.05).
CI: 1.14, 1.35, P < 0.00001)], and ≥4.5 g [(RR = 1.20, 95% CI:
1.11, 1.30, P < 0.0001)], indicating a better effect in the treatment
group than in the control group in three subgroups (Table 5). 3.3.3. Frequency of angina pectoris
Ten RCTs (18–24, 26, 31, 33), including 836 patients, reported
the frequency of angina pectoris, and the results of the
3.3.2. Duration of angina pectoris heterogeneity test suggested significant heterogeneity (P < 0.00001,
Ten RCTs (18–24, 26, 31, 33), including 836 patients, reported I 2 = 96%). We explored the source of heterogeneity through
the angina pectoris duration, and the results of the heterogeneity sensitivity analysis. The exclusion of any study had no prominent
test suggested significant heterogeneity (P < 0.00001, I 2 = 96%). effect on the heterogeneity results, indicating no effect of
We explored the source of heterogeneity through sensitivity interstudy heterogeneity on the results, so we combined them
analysis. The exclusion of any study had no significant effect on through a random-effects model. Since the measurement units of
the heterogeneity results, indicating that interstudy heterogeneity angina pectoris frequency differed in different research centers,
did not affect the results, so we used a random-effects model to SMD was used as a valid indicator for meta-analysis. Results
combine them. Results displayed lower angina pectoris duration indicated lower angina pectoris frequency in the treatment group
in the treatment group than that in the control group [(MD = than in the control group [(SMD = −2.48, 95% CI: −3.42, −1.54,
−0.2.15, 95% CI: −2.91, −1.04, P < 0.00001), Table 6]. In terms P < 0.00001), Table 8]. In terms of the treatment course, among
of the treatment course, among all the included studies, the all the included studies, the treatment course in Tang (19) was
treatment course in Tang (19) was 180 days, while it was 28 or 180 days, while in other studies, it was 28 or 30 days. After
30 days in other studies. After excluding Tang (19), I 2 was found excluding Tang (19), I 2 was found to be 96%, and the
to be 96%, and the heterogeneity did not change significantly. heterogeneity did not change significantly. We divided them into
We divided them into three subgroups, <3, ≥3 and <4.5, and three subgroups: <3, ≥3 and <4.5, and ≥4.5 g subgroups (Table 9)
≥4.5 g (Table 7), according to the daily dose of the Danshen according to the daily dose of the Danshen tablet. Heterogeneity

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TABLE 2 Characteristics of the intervention measures.

Study Interventions of the treatment group Interventions of the control group

Chinese medicine Western medicine Western medicine
Su B 2021 (17) Danlou tablet 1.2 g, tid Aspirin 300 mg/time, tid; Aspirin 300 mg/time, tid;
Atorvastatin, 20 mg/time, qd Atorvastatin, 20 mg/time, qd
Tan JY 2013 (18) Danlou tablet 1.5 g, bid Aspirin 100 mg, qd; Aspirin 100 mg, qd;
Simvastatin 20 mg, qd; Simvastatin 20 mg, qd;
Isosorbide nitrate 10 mg, tid Isosorbide nitrate 10 mg, tid
Kang RK 2013 (19) Danlou tablet 1.5 g, tid Hypoglycemic, Hypoglycemic,
Lipid-regulating Lipid-regulating
Wang L 2015 (20) Danlou tablet 1.5 g, tid Bayaspirin 100 mg, qd; Bayaspirin 100 mg, qd;
Atorvastatin calcium 20 mg, qd Atorvastatin calcium 20 mg, qd
Polyvir, 75 mg, qd; Polyvir, 75 mg, qd;
Low-molecular-weight heparin calcium 6000 iu, bid, Low-molecular-weight heparin calcium 6000 iu, bid,
subcutaneous injection; subcutaneous injection;
Metoprolol succinate 23.75–47.5 mg, qd Metoprolol succinate 23.75–47.5 mg, qd
Wang SH 2012 (21) Danlou tablet 1. 5 g, bid Aspirin 100 mg, qd; Aspirin 100 mg, qd;
Simvastatin 20 mg, qd; Simvastatin 20 mg, qd;
Isosorbide nitrate 10 mg, tid Isosorbide nitrate 10 mg, tid
Wang WL 2021 (22) Danlou tablet 1.5 g, bid Aspirin sustained-release tablets; Aspirin sustained-release tablets;
Isosorbide mononitrate 20 mg, bid Isosorbide mononitrate 20 mg, bid
Wang YH 2018 (23) Danlou tablet 1.5 g, bid Aspirin 100 mg, qd; Aspirin 100 mg, qd;
`Rosuvastatin 10 mg, qd; Rosuvastatin 10 mg, qd;
Isosorbide nitrate 10 mg, tid Isosorbide nitrate 10 mg, tid
Wei Q 2015 (24) Danlou tablet 1.5 g, bid Aspirin enteric-coated tablet/Bayaspirin 100 mg, qd; Aspirin enteric-coated tablet/Bayaspirin 100 mg, qd;
Clopidogrel 75 mg, qd; Clopidogrel 75 mg, qd;
Simvastatin 20 mg, qd; Simvastatin 20 mg, qd;
Isosorbide nitrate 10 mg, tid Isosorbide nitrate 10 mg, tid
Metoprolol tartrate tablets 25 mg, bid Metoprolol tartrate tablets 25 mg, bid
Xing XH 2020 (25) Danlou tablet 1.5 g, tid Statins, Statins,
coronary vasodilators coronary vasodilators
Zang GP 2018 (26) Danlou tablet 1.5 g, tid Aspirin tablet 500 mg, qd; Aspirin tablet 500 mg, qd;
Atorvastatin calcium 20 mg, qd; Atorvastatin calcium 20 mg, qd;
Isosorbide mononitrate sustained-release tablets 60 mg, qd Isosorbide mononitrate sustained-release tablets 60 mg, qd
Ma XF 2017 (27) Danlou tablet 1.5 g, tid Isosorbide mononitrate tablets 20 mg, tid Isosorbide mononitrate tablets 20 mg, tid
Ren DZ 2014 (28) Danlou tablet 1.2 g, tid Aspirin; low-molecular-weight heparin calcium; nitrates; Aspirin; low-molecular-weight heparin calcium; nitrates; β-
βblockers blockers
Tian CH 2017 (29) Danlou tablet 2.5 g, tid Trimetazidine hydrochloride tablets 20 mg, tid Trimetazidine hydrochloride tablets 20 mg, tid
Wang M 2019 (30) Danlou tablet 1.5 g, qd Aspirin 100 mg, qd; Aspirin 100 mg, qd;
Atorvastatin calcium 20 mg, qd Atorvastatin calcium 20 mg, qd
Yang XY 2014 (31) Danlou tablet 0. 5–1 g, bid Aspirin 150 mg, qd; Aspirin 150 mg, qd;
Atorvastatin 10 mg, qd Atorvastatin 10 mg, qd
Zang JH 2018 (32) Danlou tablet 1.5 g, tid Simvastatin pills 10 mg, qd Simvastatin pills 10 mg, qd
Zhou MJ 2013 (33) Danlou tablet 0. 5–1 g, qd Aspirin 150 mg, qd; Aspirin 150 mg, qd;
or bid Atorvastatin 10 mg, qd Atorvastatin 10 mg, qd

TABLE 3 Risk of bias summary. TABLE 4 Meta-analysis of the effectiveness of clinical treatment.

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TABLE 5 Subgroup analysis of clinical treatment effects. TABLE 8 Meta-analysis of the frequency of angina pectoris.

TABLE 6 Meta-analysis of the duration of angina pectoris. TABLE 9 Subgroup analysis of angina pectoris frequency.

TABLE 7 Subgroup analysis of the duration of angina pectoris. TABLE 10 Meta-analysis of the degree of angina pectoris.

test results showed a loss of heterogeneity in the <3 g subgroup (P = 3.3.4. Degree of angina pectoris
0.87, I 2 = 0%) and significant heterogeneity in the ≥3 and <4.5 g Six RCTs (18–21, 25, 33), including 504 patients, reported the
subgroup (P < 0.00001, I 2 = 97%) and in the ≥4.5 g subgroup (P < angina pectoris degree (P = 0.0001, I 2 = 80%). We explored
0.00001, I 2 = 96%). Meta-analysis results, through a random-effects the source of heterogeneity through sensitivity analysis. The
model, revealed that: <3 g [(SMD = −2.75, 95% CI: −3.12, −2.38, exclusion of any study had no significant effect on the
P < 0.0001)], ≥3 and <4.5 g [(SMD = −2.50, 95% CI: −3.94, −1.07, heterogeneity results, indicating that interstudy heterogeneity did
P = 0.0006)], and ≥4.5 g [(SMD = −2.27, 95% CI: −4.88, 0.33, P = not affect the result; thus, we combined them through a random-
0.09)], indicating lower angina pectoris frequency in the treatment effect model. Since the measurement units of the degree of
group than the control group when the daily dose of Danlou angina pectoris differed in different research centers, SMD could
tablets was <4.5 g (P < 0.05), and there was no difference when the be used as a valid indicator in meta-analysis. Results displayed a
daily dose of Danlou tablets was ≥4.5 g (P > 0.05). lower angina pectoris degree in the treatment group vs. the

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TABLE 11 Meta-analysis of TC. for the control group [(MD = −0.64, 95% CI: −0.76, −0.51, P <
0.00001), Table 13].

3.3.8. High-density lipoprotein cholesterol

Three RCTs (24, 28, 32), including 228 patients, reported
HDL-C. No heterogeneity could be seen from the heterogeneity
test results (P = 0.44, I 2 = 0%). Through a fixed-effect model,
results displayed higher HDL-C for the treatment group than
that for the control group [(MD = 0.16, 95% CI: 0.11, 0.21, P <
0.00001), Table 14].

3.3.9. Adverse events

Seven RCTs (19, 20, 24, 25, 27, 28, 30), including 538 patients,
reported an adverse event rate, of which four RCTs (19, 20, 24, 28)
TABLE 12 Meta-analysis of TG. showed no adverse events in any of the groups. Meta-analysis
results of adverse events reported in the remaining three RCTs
(25, 27, 30) are presented in Table 15, indicating fewer adverse
events in the treatment group than those in the control group
[(RR = 0.46, 95% CI: 0.24, 0.88, P = 0.02), Table 15]. The
proportion of adverse events is shown in Table 16.

3.4. Subgroup analysis

We conducted a subgroup analysis based on the course of

treatment (Table 17). In the case of the clinical treatment effect,
we used a fixed-effect model, which showed greater efficacy than
the control group in the subgroups of 28, 30, and 56 days.
However, the 180-day subgroup showed no difference in efficacy
control group [(SMD = −0.96, 95% CI: −1.39, −0.53, P < 0.0001), between the treatment and control groups [28 days: (RR = 1.24,
Table 10]. 95% CI: 1.16, 1.34, P < 0.00001); 30 days: (RR = 1.19, 95% CI:
1.11, 1.29, P < 0.00001); 56 days: (RR = 1.20, 95% CI: 1.06, 1.36,
P = 0.0003); 180 days: (RR = 1.20, 95% CI: 0.99, 1.44, P = 0.06)].
3.3.5. Total cholesterol
In the case of the duration of angina pectoris, we used a
Three RCTs (24, 28, 32) including 228 patients reported TC.
random-effects model, which showed greater efficacy than that of
No heterogeneity could be seen from the heterogeneity test
the control group in the subgroups of 28 and 30 days, but the
results (P = 0.63, I 2 = 0%). Through a fixed-effect model, the
180-day subgroup showed no difference in efficacy between the
results displayed a lower TC for the treatment group than that
treatment and control groups [28 days: (MD = −1.69, 95% CI:
for the control group [(MD = −0.71, 95% CI: −0.92, −0.51, P <
−2.29, −1.09, P < 0.00001); 30 days: (MD = −3.69, 95% CI:
0.00001), Table 11].
−4.33, −3.05, P < 0.00001); 180 days: (MD = −0.40, 95% CI:
−1.15, 0.35, P = 0.30)]. In the case of the frequency of angina
3.3.6. Triglyceride pectoris, we used a random-effects model, and the results
Three RCTs (24, 28, 32), including 228 patients, reported TG. indicated that each subgroup showed greater efficacy than the
No heterogeneity could be seen from the heterogeneity test results control group [28 days: (SMD = −2.22, 95% CI: −3.43, −1.01,
(P = 0.47, I 2 = 0%). Through a fixed-effect model, the results P = 0.0003); 30 days: (SMD = −3.59, 95% CI: −5.02, −2.16, P <
displayed a lower TG for the treatment group than that for the 0.0001); 180 days: (SMD = −0.67, 95% CI: −1.31, −0.03, P =
control group [(MD = −0.38, 95% CI: −0.53, −0.22, P < 0.00001), 0.04%)]. In the case of the degree of angina pectoris, we used a
Table 12]. random-effect model. The results showed that the subgroups
with 28 and 30 days of treatment showed greater efficacy than
3.3.7. Low-density lipoprotein cholesterol the control group. However, the 180-day subgroup showed no
Three RCTs (24, 28, 32), including 228 patients, reported LDL- difference in efficacy between the treatment and control groups
C. No heterogeneity could be seen from the heterogeneity test [28 days: (SMD = −0.84, 95% CI: −1.45, −0.22, P = 0.008); 30
results (P = 0.50, I 2 = 0%). Through a fixed-effect model, the days: (SMD = −1.42, 95% CI: −2.01, −0.83, P < 0.00001); 180
results displayed lower LDL-C for the treatment group than that days: (SMD = −0.26, 95% CI: −0.89, 0.36, P = 0.41)].

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Mao et al. 10.3389/fcvm.2023.1100006

TABLE 13 Meta-analysis of LDL-C.

TABLE 14 Meta-analysis of HDL-C.

3.5. Sensitivity analysis degree), blood lipid status (TC, TG, LDL-C, and HDL-C), and
adverse events. Results showed no significant change in the size
Through STATA.14 software, sensitivity analysis was conducted of the effect of the outcome indicators after excluding any
for all outcome indicators, including clinical treatment effect, study, indicating reliable and stable meta-analysis results
improvement of angina pectoris (pain frequency, duration, and (Figures 2–10).

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TABLE 15 Meta-analysis of adverse events.

involved in the pathogenesis of CHD. Therefore, while improving

TABLE 16 Proportion of the adverse events.
the myocardial blood supply, it is essential to regulate the
Adverse event Treatment group Control group concentration of blood lipids, enhance the cardiomyocyte’s
(n = 274) (n = 264) tolerance to ischemia, and improve the state of blood
Abnormal blood routine [n (%)] 1 (0.0036) 4 (0.0152)
hypercoagulation (34). Guideline-recommended drugs such as
Abdominal distension [n (%)] 1 (0.0036) 4 (0.0152)
aspirin, statins, angiotension converting enzyme inhibitors (ACEI)/
Diarrhea [n (%)] 4 (0.0146) 5 (0.0189)
Nausea, vomiting [n (%)] 2 (0.0073) 4 (0.0152)
angiotonin receptor blockers (ARBs), and β-blockers are widely
Thirst [n (%)] 0 (0) 2 (0.0076) used to prevent and treat CHD (35). However, the actual use
Abnormal liver function [n (%)] 1 (0.0036) 3 (0.0114) situation and clinical efficacy are not optimistic (36, 37), related to
Erythra [n (%)] 2 (0.0073) 2 (0.0076) individual patient differences, compliance, and adverse drug
Insomnia [n (%)] 1 (0.0036) 1 (0.0038) reactions (7, 38). Therefore, guideline-based standardized therapy
Add up [n (%)] 8 (0.0292) 23 (0.0871)
should also consider individual patient differences, and seeking
complementary or alternative therapies for CHD is necessary.
In the concept of TCM, CHD belongs to “Xiong bi” (chest
3.6. Publication bias obstruction) and “zhen xin tong” (absolute heart pain) and is the
disease of intermingled deficiency and excess, with asthenia in
A funnel plot detected publication bias in the primary outcome origin and superficiality. The deficiency is dominated by qi
indicators. As shown in the figure, the asymmetric funnel plot deficiency, and the excess is dominated by blood stasis and
indicated that publication bias might exist (Figure 11). Subsequently, phlegm turbidity (39, 40). Danlou tablets are composed of
Egger’s and Begg’s tests were used. Egger’s test (P = 0.0726 > 0.05) Danshen (Radix Salviae Miltiorrhiae), Gualou (Fructrs
suggested no publication bias, and Begg’s test (P = 0.0487 < 0.05) Trichosanthis), Gegen (Radix Puerariae), Chishao (Radix Paeoniae
suggested publication bias. To sum up, publication bias exists. Rubra), Xiebai (Bulbus Allii Macrostemi), Chuanxiong (Rhizoma
Chuanxiong), Yujin (Radix Curcumae), Zexie (Rhizoma Alismatis),
Huangqi (Radix Astragali), and Gusuibu (Rhizoma Drynariae),
3.7. Overall quality of evidence by GRADE which has the effect of relieving chest, dispelling phlegm,
dispersing knot, and activating blood to remove stasis. Therefore,
The available evidence was evaluated using the GRADE method. it plays a good role in treating CHD of blood stasis and phlegm
Clinical treatment effect, improvement of angina pectoris (duration, turbidimetry syndromes (41). Experimental studies have fully
frequency, and degree), and incidence of adverse events were rated as exemplified that Danlou tablets can reduce myocardial ischemia
“low.” The downgraded contents included the following: (1) some and reperfusion injury (42), regulate procholesterol efflux, and
studies did not describe randomization, and only one study perform anti-inflammation by activating the PPARα/ABCA1
described participants, personnel, and outcome assessments; and signaling pathway; concurrently, the NF-κB signaling pathway is
(2) publication bias from a funnel plot test was shown. prevented, thereby playing its role in alleviating atherosclerosis
Improvement of blood lipids (TC, TG, LDL-C, and HDL-C) was (13). The main chemical components of Danlou tablets include
rated as “very low,” and the downgraded contents included the flavonoids, tanshinones, protostane triterpenoids, and paeoniflorin
following: (1) some studies did not describe randomization, and (43), which have antioxidant, antiplatelet aggregation, and
only one study described participants, personnel, and outcome antithrombosis effects and are the main bioactive compounds used
assessments; (2) due to the small number of studies included and to treat cardiovascular diseases (6).
the wide confidence interval, the downgrade was carried out; and Our results indicated a better effect of Danlou tablets combined
(3) publication bias from a funnel plot test was shown (Table 18). with Western medicine than Western medicine alone in treating
CHD, mainly in improving the clinical treatment effect, reducing
the angina pectoris attack frequency, shortening the angina
4. Discussion pectoris attack duration, reducing the angina pectoris degree,
reducing TC, TG, and LDL-C levels, and improving HDL-C
The deposition of coronary artery lipids, the formation of levels. We evaluated the quality of evidence for outcome
atherosclerotic plaque, and disorders of lipid metabolism are indicators using the GRADE method. The quality of evidence for

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TABLE 17 Subgroup analysis results.

Outcome index Course (days) Number of studies Heterogeneity Meta-analysis results

I 2
P Model 95%CI P
Clinical treatment effect 28 6 7% 0.37 RR Fixed 1.24 (1.16, 1.34) <0.00001
30 5 0% 0.99 effect 1.19 (1.11, 1.29) <0.00001
56 1 NA NA 1.20 (1.06, 1.36) 0.003
180 2 0% 0.56 1.20 (0.99, 1.44) 0.06
Duration of angina pectoris 28 6 89% <0.00001 MD −1.69(−2.29, −1.09) <0.00001
30 3 67% 0.05 Random −3.69(−4.33, −3.05) <0.00001
180 1 NA NA effect −0.40(−1.15, 0.35) 0.30
Frequency of angina pectoris 28 6 96% <0.00001 SMD −2.22(−3.43, −1.01) 0.0003
30 3 94% <0.00001 Random −3.59(−5.02, −2.16) <0.00001
180 1 NA NA effect −0.67(−1.31, −0.03) 0.04
Degree of angina pectoris 28 3 80% 0.006 SMD −0.84(−1.45, −0.22) 0.008
30 2 72% 0.06 Random −1.42(−2.01, −0.83) <0.00001
180 1 NA NA effect −0.26(−0.89, 0.36) 0.41

NA, data unavailable; MD, mean difference; SMD, standard mean difference; CI, confidence interval. The bold font indicates a statistically significant difference between the
two treatments.

FIGURE 2
Sensitivity analysis of the effectiveness of clinical treatment.

clinical treatment effect, improvement of angina pectoris (duration, between the two groups when the dose of Danlou tablets was
frequency, and degree), and incidence of adverse events were ≥4.5 g per day (P > 0.05). Since the observation time of one
“Low.” The quality of evidence regarding the improvement of study (19) was 6 months, much longer than that of the other
blood lipids (TC, TG, LDL-C, and HDL-C) was “very low.” studies, we suspected that the treatment course affected the
Clinical treatment efficacy is a common index for evaluating the difference between the two groups. However, when we excluded
TCM curative effect, which can reflect the overall therapeutic this study, the results did not change, and the sensitivity analysis
effect. The results showed a better clinical treatment effect of showed that excluding any of the studies would not change the
Danlou tablets combined with Western medicine than in treating robustness of the results. We conducted a subgroup analysis
CHD alone. Subgroup analysis results showed that a high dose based on the course of treatment to explore the effects of
(≥4.5 g per day) or a low dose (<4.5 g per day) of Danlou tablets different treatments on the results. The results showed the worst
could improve the therapeutic effect. Combined with the effect outcome for 180 days of treatment, and even no difference in
size, the efficacy of a low dose was better than that of a high efficacy from the control group, which may be associated with
dose. It can be seen from the results of the meta-analysis that two studies of 180 days in the high-dose group (≥4.5 g per day)
adding Danlou tablets to conventional Western medicine (19, 32). Therefore, low-dose Danlou tablets may have a better
treatment could improve the frequency, duration, and pain effect on angina pectoris. Dyslipidemia is a significant critical
degree of angina pectoris. Subgroup analysis results displayed no risk factor for CHD, and prevention and reasonable control of
difference in the angina pectoris frequency and the duration dyslipidemia can significantly change the morbidity and

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FIGURE 3
Sensitivity analysis of the frequency of angina pectoris.

FIGURE 4
Sensitivity analysis of the duration of angina pectoris.

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Mao et al. 10.3389/fcvm.2023.1100006

FIGURE 5
Sensitivity analysis of the degree of angina pectoris.

FIGURE 6
Sensitivity analysis of TC.

mortality of cardiovascular diseases (44, 45). Meta-analysis results reactions were conducted for a short period (6 months in one
showed that Danlou tablets had positive efficacy in reducing TC, study, 8 weeks in one study, and 4 weeks in the others). Adverse
TG, and LDL-C levels and improving HDL-C levels. Despite the events were observed in only three studies, so more long-term
high homogeneity of the study results and robust results by follow-up studies are needed to evaluate the impact of Danlou
sensitivity analysis, only three studies reported changes in blood tablets on adverse events.
lipids with a small sample size; therefore, more large clinical Heterogeneity analysis indicated that the results of the
studies are required to confirm this conclusion. Adverse events heterogeneity test in regard to the frequency, duration, and
are crucial indicators to evaluate the feasibility of treatment. degree of angina pectoris showed significant heterogeneity;
Meta-analysis results showed no increase in the incidence of although subgroup analysis based on the dose of the Danshen
adverse events from Danlou tablets, but it was not clear whether tablet was performed, the heterogeneity was not eliminated. We
Danlou tablets could reduce the adverse reactions caused by also analyzed heterogeneity through the course of treatment.
Western drugs because most of the studies reporting adverse Since one of the included studies (19) had a course of 6 months

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FIGURE 7
Sensitivity analysis of TG.

FIGURE 8
Sensitivity analysis of LDL-C.

FIGURE 9
Sensitivity analysis of HDL-C.

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FIGURE 10
Sensitivity analysis of adverse events.

FIGURE 11
Funnel plot of clinical treatment effects.

TABLE 18 GRADE summary table of outcome indicator evidence quality.

and the remaining studies had a course of 28 or 30 days, Our meta-analysis had the following limitations: (1) The
heterogeneity remained the same when we excluded the study Western medicine treatment regimens in all the studies were not
with a long course. Therefore, the dose and course of treatment identical, and the age span of the patients in the study was large,
of Danlou tablets may not be the primary sources of which may increase clinical heterogeneity. (2) The blind method
heterogeneity. Through a detailed comparison of the and concealment of distribution concealment were not reported
characteristics of the included studies, it was found that in most studies, which may lead to a bias in the efficacy of
differences in Western medicine treatment options may have Danlou tablets. (3) A small sample size was included in most
brought about more pronounced heterogeneity since the types studies conducted in just one clinical trial center.
and doses of Western oral medicine were not wholly the same
among patients in all studies, and some studies did not report
the name and dose of western medicine. In addition, there was 5. Conclusion
also a specific difference in the patients’ ages, which ranged from
48.88 ± 5.01 to 69.93 ± 2.04, with a large span. Despite the The current evidence suggests that the combination of Danlou
heterogeneity of some outcome indicators, sensitivity analysis tablets and Western medicine can enhance the efficacy of CHD and
showed that all meta-analysis results were robust. does not increase adverse events. However, because of the limited

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Mao et al. 10.3389/fcvm.2023.1100006

number and quality of the included studies, the results of our study Conflicts of interest
should be treated with caution. Further large-scale RCTs are
necessary to verify the benefits of this approach. The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Author contributions The reviewer Lin Li declared a shared affiliation with the
authors RW and YL to the handling editor at the time of review.
Conception and design: WM, PL, and RW; design of data
synthesis analysis scheme: WM, KM, PL, RW, YL, and JH;
manuscript writing: WM, PL, and ZF; and final approval of
manuscript: JW, WM, PL, and RW. All authors contributed to
Publisher’s note
the article and approved the submitted version.
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
Funding
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
This study was financially supported by the Zhejiang Provincial
or endorsed by the publisher.
Natural Science Foundation of China under Grant no.
LYQ20H300001.

Supplementary material
Acknowledgments
The Supplementary Material for this article can be found
The authors would like to thank Freescience (www.home-for- online at https://www.frontiersin.org/articles/10.3389/fcvm.2023.
researchers.com) for the help with the English language. 1100006/full#supplementary-material.

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